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  • 1.
    Bromée, T
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Farmakologi 2.
    Kukkonen, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Fysiologi.
    Andersson, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Conlon, JM
    Larhammar, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Farmakologi 2.
    Pharmacological characterization of ligand-receptor interactions at the zebrafish bradykinin receptor2005In: Br J Pharmacol, Vol. 144, p. 11-16Article in journal (Refereed)
  • 2.
    Bromée, Torun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sjödin, Paula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Boswell, Tim
    Larsson, Tomas A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Salaneck, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Zoorob, Rima
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neuropeptide Y-family receptors Y6 and Y7 in chicken: Cloning, pharmacological characterization, tissue distribution and conserved synteny with human chromosome region2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, no 9, p. 2048-2063Article in journal (Refereed)
    Abstract [en]

    The peptides of the neuropeptide Y (NPY) family exert their functions, including regulation of appetite and circadian rhythm, by binding to G-protein coupled receptors. Mammals have five subtypes, named Y1, Y2, Y4, Y5 and Y6, and recently Y7 has been discovered in fish and amphibians. In chicken we have previously characterized the first four subtypes and here we describe Y6 and Y7. The genes for Y6 and Y7 are located 1 megabase apart on chromosome 13, which displays conserved synteny with human chromosome 5 that harbours the Y6 gene. The porcine PYY radioligand bound the chicken Y6 receptor with a Kd of 0.80 ± 0.36 nm. No functional coupling was demonstrated. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue. Porcine PYY bound chicken Y7 with a Kd of 0.14 ± 0.01 nm (mean ± SEM), whereas chicken PYY surprisingly had a much lower affinity, with a Ki of 41 nm, perhaps as a result of its additional amino acid at the N terminus. Truncated peptide fragments had greatly reduced affinity for Y7, in agreement with its closest relative, Y2, in chicken and fish, but in contrast to Y2 in mammals. This suggests that in mammals Y2 has only recently acquired the ability to bind truncated PYY. Chicken Y7 has a much more restricted tissue distribution than other subtypes and was only detected in adrenal gland. Y7 seems to have been lost in mammals. The physiological roles of Y6 and Y7 remain to be identified, but our phylogenetic and chromosomal analyses support the ancient origin of these Y receptor genes by chromosome duplications in an early (pregnathostome) vertebrate ancestor.

  • 3.
    Bromée, Torun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Venkatesh, Byrappa
    Brenner, Sidney
    Postlethwait, John H.
    Yan, Yi-Lin
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Uneven Evolutionary Rates of Bradykinin B1 and B2 Receptors in Vertebrate Lineages2006In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 373, p. 100-108Article in journal (Refereed)
    Abstract [en]

    Bradykinin acts through two receptor subtypes in mammals and generates a variety of responses including pain, inflammation and hypotension. The evolutionary history of the bradykinin system has been unclear due to shortage of information outside mammals. We describe here two receptor subtypes and the bradykinin precursor in three species of bony fish (the zebrafish Danio rerio, the Japanese pufferfish Takifugu rubripes, and the green spotted pufferfish Tetraodon nigroviridis) and chicken and analyze the relationships to mammals by a combination of phylogeny, conserved synteny and exon–intron organization. All of these species have two receptor genes located close to each other in a tandem formation, with the B2 gene 5′ to the B1 gene, in chromosomal regions displaying conserved synteny between the species (albeit conservation of synteny in zebrafish is still unclear due to poor genome assembly). The evolutionary rate differs between the two genes as well as between lineages leading to differing pharmacological properties for both B1 and B2 across vertebrate classes. Also the bradykinin precursor gene was identified in all of these species in a chromosome region with conserved synteny. The tissue distribution of mRNA in T. rubripes is similar for B1 and B2, suggesting more similar regulation for the two genes than in mammals. In conclusion, the receptor tandem duplication predates the divergence of ray-finned fish and tetrapods and no additional duplicates of the receptors or bradykinin seem to have survived the ray-finned fish tetraploidization.

  • 4.
    Cardoso, Joao C. R.
    et al.
    Univ Algarve, Ctr Marine Sci, Comparat Endocrinol & Integrat Biol, Campus Gambelas, Faro, Portugal..
    Bergqvist, Christina A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Felix, Rute C.
    Univ Algarve, Ctr Marine Sci, Comparat Endocrinol & Integrat Biol, Campus Gambelas, Faro, Portugal..
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Corticotropin-releasing hormone family evolution: five ancestral genes remain in some lineages2016In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 57, no 1, p. 73-86Article in journal (Refereed)
    Abstract [en]

    The evolution of the peptide family consisting of corticotropin-releasing hormone ( CRH) and the three urocortins ( UCN1-3) has been puzzling due to uneven evolutionary rates. Distinct gene duplication scenarios have been proposed in relation to the two basal rounds of vertebrate genome doubling ( 2R) and the teleost fish-specific genome doubling ( 3R). By analyses of sequences and chromosomal regions, including many neighboring gene families, we show here that the vertebrate progenitor had two peptide genes that served as the founders of separate subfamilies. Then, 2R resulted in a total of five members: one subfamily consists of CRH1, CRH2, and UCN1. The other subfamily contains UCN2 and UCN3. All five peptide genes are present in the slowly evolving genomes of the coelacanth Latimeria chalumnae ( a lobe-finned fish), the spotted gar Lepisosteus oculatus ( a basal ray-finned fish), and the elephant shark Callorhinchus milii ( a cartilaginous fish). The CRH2 gene has been lost independently in placental mammals and in teleost fish, but is present in birds ( except chicken), anole lizard, and the nonplacental mammals platypus and opossum. Teleost 3R resulted in an additional surviving duplicate only for crh1 in some teleosts including zebrafish ( crh1a and crh1b). We have previously reported that the two vertebrate CRH/UCN receptors arose in 2R and that CRHR1 was duplicated in 3R. Thus, we can now conclude that this peptide-receptor system was quite complex in the ancestor of the jawed vertebrates with five CRH/UCN peptides and two receptors, and that crh and crhr1 were duplicated in the teleost fish tetraploidization.

  • 5. Cardoso, Joao C. R.
    et al.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Comparative evolution of peptide hormone-binding GPCRs: A route to understanding functional complexity2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, no SI, p. 1-2Article in journal (Other academic)
  • 6.
    Cardoso, João C R
    et al.
    University of Algarve, Portugal.
    Félix, Rute C
    University of Algarve, Portugal.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    New insights into the evolution of vertebrate CRH (corticotropin-releasing hormone) and invertebrate DH44 (diuretic hormone 44) receptors in metazoans2014In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, no SI, p. 162-170Article in journal (Refereed)
    Abstract [en]

    The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assembled genomes from representatives of early vertebrate divergencies including elephant shark, spotted gar and coelacanth. We show here by analysis of synteny conservation that the two CRHR genes arose from a common ancestral gene in the early vertebrate tetraploidizations (2R) approximately 500 million years ago. Subsequently, the teleost-specific tetraploidization (3R) resulted in a duplicate of CRHR1 that has been lost in some teleost lineages. These results help distinguish orthology and paralogy relationships and will allow studies of functional conservation and changes during evolution of the individual members of the receptor family and their multiple native peptide agonists.

  • 7.
    Elphick, Maurice R.
    et al.
    Queen Mary Univ London, Sch Biol & Chem Sci, London E1 4NS, England..
    Mirabeau, Olivier
    Paris Sci & Lettres Res Univ, INSERM U830, Inst Curie, Genet & Biol Canc Unit, F-75005 Paris, France..
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evolution of neuropeptide signalling systems2018In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 221, no 3, article id jeb151092Article, review/survey (Refereed)
    Abstract [en]

    Neuropeptides are a diverse class of neuronal signalling molecules that regulate physiological processes and behaviour in animals. However, determining the relationships and evolutionary origins of the heterogeneous assemblage of neuropeptides identified in a range of phyla has presented a huge challenge for comparative physiologists. Here, we review revolutionary insights into the evolution of neuropeptide signalling that have been obtained recently through comparative analysis of genome/transcriptome sequence data and by 'deorphanisation' of neuropeptide receptors. The evolutionary origins of at least 30 neuropeptide signalling systems have been traced to the common ancestor of protostomes and deuterostomes. Furthermore, two rounds of genome duplication gave rise to an expanded repertoire of neuropeptide signalling systems in the vertebrate lineage, enabling neofunctionalisation and/or subfunctionalisation, but with lineage-specific gene loss and/or additional gene or genome duplications generating complex patterns in the phylogenetic distribution of paralogous neuropeptide signalling systems. We are entering a new era in neuropeptide research where it has become feasible to compare the physiological roles of orthologous and paralogous neuropeptides in a wide range of phyla. Moreover, the ambitious mission to reconstruct the evolution of neuropeptide function in the animal kingdom now represents a tangible challenge for the future.

  • 8.
    Fears, R.
    et al.
    European Academies Science Advisory Council, c/o German National Academy of Sciences Leopoldina, Halle (Saale), Germany.
    Griffin, G.
    Department of Infectious Diseases and Medicine, St George’s University of London, London, UK.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ter Meulen, V.
    European Academies Science Advisory Council, c/o German National Academy of Sciences Leopoldina, Halle (Saale), Germany.
    van der Meer, J. W. M.
    Radboud University Medical Center, Nijmegen, The Netherlands.
    Assessing and regulating homeopathic products2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 6, p. 563-565Article in journal (Other academic)
  • 9.
    Fällmar, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Neuropeptide Y/peptide YY receptor Y2 duplicate in zebrafish with unique introns displays distinct peptide binding properties2011In: Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology, ISSN 1096-4959, E-ISSN 1879-1107, Vol. 160, no 4, p. 166-173Article in journal (Other academic)
    Abstract [en]

    The neuropeptide Y-family peptides and receptors are involved in a broad range of functions including appetite regulation. Both the peptide genes and the receptor genes are known to have duplicated in early vertebrate evolution. The ancestral jawed vertebrate had 7 NPY receptors but the number varies between 4 and 7 in extant vertebrates. Herein we describe the identification of an additional NPY receptor in two fish species, zebrafish and medaka. They cluster together with the Y2 receptors in phylogenetic analyses and seem to be orthologous to each other that is why we have named them Y2-2. Their genes differ from Y2 in having introns in the coding region. Binding studies with zebrafish Y2-2 receptors show that the three endogenous peptides NPY, PYYa and PYYb have similar affinities, 0.15-0.66nM. This is in contrast to the Y2 receptor where they differed considerably from one another. N-terminally truncated NPY binds poorly and the Y2 antagonist BIIE0246 binds well to Y2-2, results that are reversed in comparison to Y2. Zebrafish Y2-2 mRNA was detected by PCR in the intestine and the eye, but not in the brain. In conclusion, we have found a novel Y2-like NPY/PYY receptor that probably arose in early teleost fish evolution.

  • 10.
    Gao, Tianle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Chinese Acad Med Sci, Inst Mat Med, Beijing, Peoples R China.
    Ma, Haisha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergman, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch2018In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 138, no 11, p. 2405-2411Article in journal (Refereed)
    Abstract [en]

    Itch is a somatosensory modality that serves to alert an organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch, whereas chemical itch was unaffected. We examined the effect of activating the NPY/Y-1 receptor system on scratch behavior in mice. We found that intrathecal administration of the Y-1 agonist [Leu(31), Pro(34)]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck compared with saline treatment, indicating that activation of the spinal NPY/Y-1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y-1 antagonist BIBO3304. Intrathecal application of the native nonselective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y-1 system dampens both mechanically and chemically induced scratching and hence is shared by the two submodalities of itch.

  • 11.
    Granas, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nordvall, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mutagenesis of the human 5-HT1B receptor: Differences from the closely related 5-HT1A receptor and the role of residue F331 in signal transduction1998In: Journal of Receptor and Signal Transduction Research, ISSN 1079-9893, E-ISSN 1532-4281, Vol. 18, no 4-6, p. 225-241p. 225-241Article in journal (Refereed)
    Abstract [en]

    We have used a combination of sequence comparisons, computer-based modeling and site-directed mutagenesis to investigate the molecular interactions involved in ligand binding and signal transduction of the human 5-HT1B receptor. Two amino acid residues, S212 in transmembrane region (TM) V and F331 in TM VI, were replaced by alanines. These amino acids are conserved in many G protein-coupled receptors and therefore likely to be important for receptor function. The mutant receptors were expressed in Chinese hamster ovary cells. The 5-HT-like agonist 5-carboxamidotryptamine (5-CT) bound with 15-fold lower affinity to the S212A mutant as compared to wild-type receptor and the antagonist methiothepin bound with 17-fold lower affinity to the F331A mutant. No reduction in the affinity of 5-HT was seen for the S212A mutant, although an equivalent mutation in the 5-HT1A receptor resulted in a 100-fold reduction of 5-HT binding. The inhibition of forskolin-stimulated cyclic AMP production by 5-HT was significantly reduced in cells expressing the F331A mutant, even though the endogenous ligand 5-HT bound with somewhat increased affinity. Methiothepin acted as an inverse agonist and increased the forskolin-stimulated cyclic AMP production at both the wild-type receptor and the mutants, and the effect was stronger on the F331A mutant. These results suggest that F331 is involved in the conformational changes necessary for signal transduction.

  • 12.
    Granqvist, Pehr
    et al.
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Unge, Patrik
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Hagenfeldt, Andrea
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Valind, Sven
    Larhammar, Dan
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Larsson, Marcus
    Sensed presence and mystical experiences are predicted by suggestibility, not by the application of weak complex transcranial magnetic fields2005In: Neuroscience Letters, Vol. in pressArticle in journal (Refereed)
  • 13. Grånäs, Charlotta
    et al.
    Nordquist, Jenny
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Farmakologi.
    Mohell, Nina
    Larhammar, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Farmakologi.
    Site-directed mutagenesis of the 5-HT1B receptor increases the affinity of 5-HT for the agonist low-affinity conformation and reduces the intrinsic acitivity of 5-HT.2001In: Eur J Pharmacol, Vol. 421, no 2, p. 69-76Article in journal (Refereed)
  • 14.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Andersson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 2.
    Larson, Earl T
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Cloning, tissue distribution, pharmacology and three-dimensional modelling of melanocortin receptors 4 and 5 in rainbow trout suggest close evolutionary relationship of these subtypes2004In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 380, no 2, p. 475-486Article in journal (Refereed)
    Abstract [en]

    The rainbow trout (Oncorhynchus mykiss) is one of the most widely used fish species in aquaculture and physiological research. In the present paper, we report the first cloning, 3D (three-dimensional) modelling, pharmacological characterization and tissue distribution of two melanocortin (MC) receptors in rainbow trout. Phylogenetic analysis indicates that these receptors are orthologues of the human MC4 and MC5 receptors. We created 3D molecular models of these rainbow trout receptors and their human counterparts. These models suggest greater divergence between the two human receptors than between their rainbow trout counterparts. The pharmacological analyses demonstrated that ACTH (adrenocorticotropic hormone) had surprisingly high affinity for the rainbow trout MC4 and MC5 receptors, whereas alpha-, beta- and gamma-MSH (melanocyte-stimulating hormone) had lower affinity. In second-messenger studies, the cyclic MSH analogues MTII and SHU9119 acted as potent agonist and antagonist respectively at the rainbow trout MC4 receptor, indicating that these ligands are suitable for physiological studies in rainbow trout. Interestingly, we found that the rainbow trout MC4 receptor has a natural high-affinity binding site for zinc ions (0.5 microM) indicating that zinc may play an evolutionary conserved role at this receptor. Reverse transcription PCR indicates that the rainbow trout receptors are expressed both in peripheral tissues and in the central nervous system, including the telencephalon, optic tectum and hypothalamus. Overall, this analysis indicates that the rainbow trout MC4 and MC5 receptors have more in common than their mammalian counterparts, which may suggest that these two receptors have a closer evolutionary relationship than the other MC receptor subtypes.

  • 15.
    Holmberg, S K S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Mikko, S
    Boswell, T
    Zoorob, R
    Larhammar, D
    Pharmacological characterization of cloned chicken neuropeptide Y receptors Y1 and Y5In: Article in journal (Refereed)
  • 16.
    Holmberg, Sara K S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Johnson, A E
    Bergqvist, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Källström, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Localization of neuropeptide Y receptor Y5 mRNA in the guinea pig brain2004In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 117, p. 61-67Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) has prominent stimulatory effects on food intake in virtually all animals that have been studied. In mammals, the effect is primarily mediated by receptors Y1 and Y5, which seem to contribute to different aspects of feeding behavior in guinea pigs and rats/mice. Interestingly, differences in receptor distribution among mammalian species have been reported. To get a broader perspective on the role of Y5, we describe here studies of guinea pig (Cavia porcellus), a species which due to its phylogenetic position in the mammalian radiation is an interesting complement to previous studies in rat and mouse. Guinea pig brain sections were hybridized with two 35S-labeled oligonucleotides complementary to Y5 mRNA. The highest expression levels of Y5 mRNA were observed in the hippocampus and several hypothalamic and brain stem nuclei implicated in the regulation of feeding, such as the paraventricular, arcuate and ventromedial hypothalamic nuclei. This contrasts with autoradiography studies that detected low Y5-like binding in these areas, a discrepancy observed also in rat and human. Y5 mRNA expression was also seen in the striatum, in great contrast to mouse and rat. Taken together, these data show that Y5 mRNA distribution displays some interesting species differences, but that its expression in feeding centers seems to be essentially conserved among mammals, adding further support for an important role in food intake.

  • 17.
    Hultqvist, Greta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Ocampo Daza, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Evolution of the Vertebrate Paralemmin Gene Family: Ancient Origin of Gene Duplicates Suggests Distinct Functions2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41850-Article in journal (Refereed)
    Abstract [en]

    Paralemmin-1 is a protein implicated in plasma membrane dynamics, the development of filopodia, neurites and dendritic spines, as well as the invasiveness and metastatic potential of cancer cells. However, little is known about its mode of action, or about the biological functions of the other paralemmin isoforms: paralemmin-2, paralemmin-3 and palmdelphin. We describe here evolutionary analyses of the paralemmin gene family in a broad range of vertebrate species. Our results suggest that the four paralemmin isoform genes (PALM1, PALM2, PALM3 and PALMD) arose by quadruplication of an ancestral gene in the two early vertebrate genome duplications. Paralemmin-1 and palmdelphin were further duplicated in the teleost fish specific genome duplication. We identified a unique sequence motif common to all paralemmins, consisting of 11 highly conserved residues of which four are invariant. A single full-length paralemmin homolog with this motif was identified in the genome of the sea lamprey Petromyzon marinus and an isolated putative paralemmin motif could be detected in the genome of the lancelet Branchiostoma floridae. This allows us to conclude that the paralemmin gene family arose early and has been maintained throughout vertebrate evolution, suggesting functional diversification and specific biological roles of the paralemmin isoforms. The paralemmin genes have also maintained specific features of gene organisation and sequence. This includes the occurrence of closely linked downstream genes, initially identified as a readthrough fusion protein with mammalian paralemmin-2 (Palm2-AKAP2). We have found evidence for such an arrangement for paralemmin-1 and -2 in several vertebrate genomes, as well as for palmdelphin and paralemmin-3 in teleost fish genomes, and suggest the name paralemmin downstream genes (PDG) for this new gene family. Thus, our findings point to ancient roles for paralemmins and distinct biological functions of the gene duplicates.

  • 18.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Callado-Perez, Amalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franzen, Ilkin E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abalo, Xesus M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transducin Duplicates in the Zebrafish Retina and Pineal Complex: Differential Specialisation after the Teleost Tetraploidisation2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0121330Article in journal (Refereed)
    Abstract [en]

    Gene duplications provide raw materials that can be selected for functional adaptations by evolutionary mechanisms. We describe here the results of 350 million years of evolution of three functionally related gene families: the alpha, beta and gamma subunits of transducins, the G protein involved in vision. Early vertebrate tetraploidisations resulted in separate transducin heterotrimers: gnat1/gnb1/gngt1 for rods, and gnat2/gnb3/gngt2 for cones. The teleost- specific tetraploidisation generated additional duplicates for gnb1, gnb3 and gngt2. We report here that the duplicates have undergone several types of subfunctionalisation or neofunctionalisation in the zebrafish. We have found that gnb1a and gnb1b are co-expressed at different levels in rods; gnb3a and gnb3b have undergone compartmentalisation restricting gnb3b to the dorsal and medial retina, however, gnb3a expression was detected only at very low levels in both larvae and adult retina; gngt2b expression is restricted to the dorsal and medial retina, whereas gngt2a is expressed ventrally. This dorsoventral distinction could be an adaptation to protect the lower part of the retina from intense light damage. The ontogenetic analysis shows earlier onset of expression in the pineal complex than in the retina, in accordance with its earlier maturation. Additionally, gnb1a but not gnb1b is expressed in the pineal complex, and gnb3b and gngt2b are transiently expressed in the pineal during ontogeny, thus showing partial temporal subfunctionalisation. These retina-pineal distinctions presumably reflect their distinct functional roles in vision and circadian rhythmicity. In summary, this study describes several functional differences between transducin gene duplicates resulting from the teleost-specific tetraploidisation.

  • 19.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Callado-Pérez, Amalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franzén, Ilkin E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abalo, Xesús M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transducin duplicates in the zebrafish retina and pineal complex: differential specialisation after the teleost tetraploidisationIn: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed)
  • 20.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Daza, Daniel Ocampo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Widmark, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abalo, Xesus M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    The vertebrate ancestral repertoire of visual opsins, transducin alpha subunits and oxytocin/vasopressin receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications2013In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 13, p. 238-Article in journal (Refereed)
    Abstract [en]

    Background: Vertebrate color vision is dependent on four major color opsin subtypes: RH2 (green opsin), SWS1 (ultraviolet opsin), SWS2 (blue opsin), and LWS (red opsin). Together with the dim-light receptor rhodopsin (RH1), these form the family of vertebrate visual opsins. Vertebrate genomes contain many multi-membered gene families that can largely be explained by the two rounds of whole genome duplication (WGD) in the vertebrate ancestor (2R) followed by a third round in the teleost ancestor (3R). Related chromosome regions resulting from WGD or block duplications are said to form a paralogon. We describe here a paralogon containing the genes for visual opsins, the G-protein alpha subunit families for transducin (GNAT) and adenylyl cyclase inhibition (GNAI), the oxytocin and vasopressin receptors (OT/VP-R), and the L-type voltage-gated calcium channels (CACNA1-L). Results: Sequence-based phylogenies and analyses of conserved synteny show that the above-mentioned gene families, and many neighboring gene families, expanded in the early vertebrate WGDs. This allows us to deduce the following evolutionary scenario: The vertebrate ancestor had a chromosome containing the genes for two visual opsins, one GNAT, one GNAI, two OT/VP-Rs and one CACNA1-L gene. This chromosome was quadrupled in 2R. Subsequent gene losses resulted in a set of five visual opsin genes, three GNAT and GNAI genes, six OT/VP-R genes and four CACNA1-L genes. These regions were duplicated again in 3R resulting in additional teleost genes for some of the families. Major chromosomal rearrangements have taken place in the teleost genomes. By comparison with the corresponding chromosomal regions in the spotted gar, which diverged prior to 3R, we could time these rearrangements to post-3R. Conclusions: We present an extensive analysis of the paralogon housing the visual opsin, GNAT and GNAI, OT/VP-R, and CACNA1-L gene families. The combined data imply that the early vertebrate WGD events contributed to the evolution of vision and the other neuronal and neuroendocrine functions exerted by the proteins encoded by these gene families. In pouched lamprey all five visual opsin genes have previously been identified, suggesting that lampreys diverged from the jawed vertebrates after 2R.

  • 21.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Franzen, Ilkin E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Eggert, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Abalo, Xesus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Evolution and expression of the phosphodiesterase 6 genes unveils vertebrate novelty to control photosensitivity2016In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 16, article id 124Article in journal (Refereed)
    Abstract [en]

    Background: Phosphodiesterase 6 (PDE6) is a protein complex that hydrolyses cGMP and acts as the effector of the vertebrate phototransduction cascade. The PDE6 holoenzyme consists of catalytic and inhibitory subunits belonging to two unrelated gene families. Rods and cones express distinct genes from both families: PDE6A and PDE6B code for the catalytic and PDE6G the inhibitory subunits in rods while PDE6C codes for the catalytic and PDE6H the inhibitory subunits in cones. We performed phylogenetic and comparative synteny analyses for both gene families in genomes from a broad range of animals. Furthermore, gene expression was investigated in zebrafish. Results: We found that both gene families expanded from one to three members in the two rounds of genome doubling (2R) that occurred at the base of vertebrate evolution. The PDE6 inhibitory subunit gene family appears to be unique to vertebrates and expanded further after the teleost-specific genome doubling (3R). We also describe a new family member that originated in 2R and has been lost in amniotes, which we have named pde6i. Zebrafish has retained two additional copies of the PDE6 inhibitory subunit genes after 3R that are highly conserved, have high amino acid sequence identity, are coexpressed in the same photoreceptor type as their amniote orthologs and, interestingly, show strikingly different daily oscillation in gene expression levels. Conclusions: Together, these data suggest specialisation related to the adaptation to different light intensities during the day-night cycle, most likely maintaining the regulatory function of the PDE inhibitory subunits in the phototransduction cascade.

  • 22.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abalo, Xesús M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evolution and expression of phosphodiesterase 6 genes show vertebrate novelty in the control of photosensitivityManuscript (preprint) (Other academic)
  • 23.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ocampo Daza, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jenny, Widmark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abalo, Xesus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The vertebrate ancestral repertoire of five visual opsins was established in the two rounds of early vertebrate genome doublingsManuscript (preprint) (Other academic)
  • 24.
    Lagman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ocampo Daza, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abalo, Xesus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Expansion of transducin subunit gene families in early vertebrate tetraploidizations2012In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 100, no 4, p. 203-211Article in journal (Refereed)
    Abstract [en]

    Hundreds of gene families expanded in the early vertebrate tetraploidizations including many gene families in the phototransduction cascade. We have investigated the evolution of the heterotrimeric G-proteins of photoreceptors, the transducins, in relation to these events using both phylogenetic analyses and synteny comparisons. Three alpha subunit genes were identified in amniotes and the coelacanth, GNAT1-3; two of these were identified in amphibians and teleost fish, GNAT1 and GNAT2. Most tetrapods have four beta genes, GNB1-4, and teleosts have additional duplicates. Finally, three gamma genes were identified in mammals, GNGT1, GNG11 and GNGT2. Of these, GNGT1 and GNGT2 were found in the other vertebrates. In frog and zebrafish additional duplicates of GNGT2 were identified. Our analyses show all three transducin families expanded during the early vertebrate tetraploidizations and the beta and gamma families gained additional copies in the teleost-specific genome duplication. This suggests that the tetraploidizations contributed to visual specialisations.

  • 25.
    Larhammar, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Farmakologi 2.
    Neuropeptide Y, evolution of2004In: The encyclopedia of endocrine diseases, Elsevier , 2004, p. 343-345Chapter in book (Other scientific)
  • 26.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Christina A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ancient Grandeur of the Vertebrate Neuropeptide Y System Shown by the Coelacanth Latimeria chalumnae2013In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 7, article id 27Article in journal (Refereed)
    Abstract [en]

    The neuropeptide Y (NPY) family receptors and peptides have previously been characterized in several tetrapods, teleost fishes, and in a holocephalan cartilaginous fish. This has shown that the ancestral NPY system in the jawed vertebrates consisted of the peptides NPY and peptide YY (PYY) and seven G-protein-coupled receptors named Y1-Y8 (Y3 does not exist). The different vertebrate lineages have subsequently lost or gained a few receptor genes. For instance, the human genome has lost three of the seven receptors while the zebrafish has lost two and gained two receptor genes. Here we describe the NPY system of a representative of an early diverging lineage among the sarcopterygians, the West Indian Ocean coelacanth Latimeria chalumnae. The coelacanth was found to have retained all seven receptors from the ancestral jawed vertebrate. The receptors display the typical characteristics found in other vertebrates. Interestingly, the coelacanth was found to have the local duplicate of the PYY gene, called pancreatic polypeptide, previously only identified in tetrapods. Thus, this duplication took place very early in the sarcopterygian lineage, before the origin of tetrapods. These findings confirm the ancient complexity of the NPY system and show that mammals have lost more NPY receptors than any other vertebrate lineage. The coelacanth has all three peptides found in tetrapods and has retained the ancestral jawed vertebrate receptor repertoire with neither gains or losses.

  • 27.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Bergqvist, Christina A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Ancestral vertebrate complexity of the opioid system2015In: Nociceptin Opioid / [ed] Gerald Litwack, Academic Press, 2015Chapter in book (Refereed)
    Abstract [en]

    The evolution of the opioid peptides and nociceptin/orphanin as well as their receptors has been difficult to resolve due to variable evolutionary rates. By combining sequence comparisons with information on the chromosomal locations of the genes, we have deduced the following evolutionary scenario: The vertebrate predecessor had one opi- oid precursor gene and one receptor gene. The two genome doublings before the ver- tebrate radiation resulted in three peptide precursor genes whereupon a fourth copy arose by a local gene duplication. These four precursors diverged to become the pre- propeptides for endorphin (POMC), enkephalins, dynorphins, and nociceptin, respec- tively. The ancestral receptor gene was quadrupled in the genome doublings leading to delta, kappa, and mu and the nociceptin/orphanin receptor. This scenario is corroborated by new data presented here for coelacanth and spotted gar, rep- resenting two basal branches in the vertebrate tree. A third genome doubling in the ancestor of teleost fishes generated additional gene copies. These results show that the opioid system was quite complex already in the first vertebrates and that it has more components in teleost fishes than in mammals. From an evolutionary point of view, nociceptin and its receptor can be considered full-fledged members of the opioid system. 

  • 28.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lagman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Turtle ghrelin2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 6, p. 524-525Article in journal (Refereed)
  • 29.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundin, Lars G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Tacka dna-explosionen för att du finns2012In: Forskning & Framsteg, ISSN 0015-7937, Vol. 47, no 9, p. 34-37Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Vid några avgörande ögonblick för ungefär en halv miljard år sedan fick våra föregångare plötsligt massor av nya gener. Spåren syns fortfarande tydligt i vår arvsmassa.

  • 30.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nordström, Karin
    School of Molecular and Biomedical Science, The University of Adelaide, Adelaide SA 5005, Australia .
    Larsson, Tomas A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Evolution of vertebrate rod and cone phototransduction genes2009In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 364, no 1531, p. 2867-2880Article, review/survey (Refereed)
    Abstract [en]

    Vertebrate cones and rods in several cases use separate but related components for their signal transduction (opsins, G-proteins, ion channels, etc.). Some of these proteins are also used differentially in other cell types in the retina. Because cones, rods and other retinal cell types originated in early vertebrate evolution, it is of interest to see if their specific genes arose in the extensive gene duplications that took place in the ancestor of the jawed vertebrates (gnathostomes) by two tetraploidizations (genome doublings). The ancestor of teleost fishes subsequently underwent a third tetraploidization. Our previously reported analyses showed that several gene families in the vertebrate visual phototransduction cascade received new members in the basal tetraploidizations. We here expand these data with studies of additional gene families and vertebrate species. We conclude that no less than 10 of the 13 studied phototransduction gene families received additional members in the two basal vertebrate tetraploidizations. Also the remaining three families seem to have undergone duplications during the same time period but it is unclear if this happened as a result of the tetraploidizations. The implications of the many early vertebrate gene duplications for functional specialization of specific retinal cell types, particularly cones and rods, are discussed.

  • 31.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dores, Robert M
    University of Denver.
    Evolution of the opioid system.2013In: Handbook of Biologically Active Peptides / [ed] A. J. Kastin, Academic Press, 2013, 2nd, p. 1562-1569Chapter in book (Refereed)
  • 32.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Vanden Broeck, Jozef
    Peptide hormone and receptor evolution2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 153, no 1-3, p. 147-Article in journal (Refereed)
    Abstract [en]

    An important and fascinating theme that unifies both invertebrate and vertebrate endocrinologists is that of the evolution of peptide precursor and receptor genes. Peptide signalling plays a crucial role in processes that control decisive physiological events in organisms as divergent as yeast and mammals. The majority of small neuronal/endocrine peptides exert their functions via an interaction with heptahelical membrane receptors belonging to the G protein-coupled receptor superfamily, a large and diverse signal transducing protein category which has very ancient evolutionary roots. Most of the larger peptides and growth factors function via other well-conserved receptor classes that contain only a single transmembrane segment. The symposium on peptide hormone and receptor evolution brought together scientists studying peptide–receptor evolution in widely divergent metazoans.

    Two State-of-the-Art lectures gave overviews of current knowledge of peptide and receptor gene evolution. The sequencing and annotation of entire animal genomes constitutes a very exciting development that have already revolutionized the general views on metazoan macroevolution. The resulting burst of molecular data represents an impressive boost of novel opportunities for comparative and functional genomics research. Several vertebrate peptide and receptor families were described by Dan Larhammar to have multiplied in the 1–2 basal vertebrate tetraploidizations and in a third tetraploidization in ray-finned fishes before the radiation of teleosts. Families proposed to have multiplied in these events include NPY, tachykinins, opioid peptides, as well as the receptors for these three peptide families. The dynamics of coevolutionary change were discussed by Jozef Vanden Broeck based on several examples of peptide–receptor partners that show conservation across the protostomian–deuterostomian barrier. These examples include peptides belonging to the NPY, tachykinin, glycoprotein hormone and insulin-related peptide families, and their respective receptors.

    Additional examples of coevolution between peptides and their corresponding receptors in insects (the mosquito Aedes aegypti) and chelicerates (the tick Boophilus microplus) were presented by Ron Nachman. His detailed analysis of peptide receptor pharmacology has led to the production and selection of peptidomimetic compounds which specifically activate a particular receptor, while showing enhanced resistance against peptidases. This type of work may ultimately lead to the creation of novel, environmentally safe pest agents for insect management. In two other presentations, the evolution of two quite complex vertebrate peptide receptor systems were discussed. The five divergent and presumably ancient melanocortin receptors found in mammals have only three orthologues in the two sharks investigated so far (Angela Baron). Both the ά-MSH receptor MC1 and the ACTH receptor MC2 still remain to be identified or may have been lost or become widely divergent. The evolution of the large VIP/PACAP/secretin family (Florbela Vieira) involves duplicate PACAP genes in teleost fishes, whereas only a single VIP gene seems to exist. The PACAP gene and its chromosomal environment is more strongly conserved than the VIP gene. Invertebrates only have a single member most closely resembling PACAP.

    The concluding discussion largely revolved around the proposed tetraploidizations in early vertebrate evolution. While some hesitation still lingers, there is nevertheless no alternative explanation that can account better than the chromosome duplication (and tetraploidization) scenario for the extensive chromosome similarities and the high number of gene duplications that arose before gnathostomatous radiation. Additional gene duplications in early vertebrates were mentioned leading to the somatostatin 2-urotensin II gene pair and the somatostain 1-urotensin II-related peptide gene pair (Hervé Tostivint). Also the possible orthology relationships between peptides described in invertebrates, particularly insects, and vertebrates were discussed. Undoubtedly, definitive orthology relationships of neuropeptide precursor genes between protostomes and deuterostomes are often difficult to determine from sequence comparisons only, and will hopefully be aided by information on chromosome locations and gene neighbours.

  • 33.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Unexpected multiplicity of QRFP receptors in early vertebrate evolution2014In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, p. 337-Article in journal (Refereed)
    Abstract [en]

    The neuropeptide QRFP, also called 26RFa, and its G protein-coupled receptor GPR103 have been identified in all vertebrates investigated. In mammals, this peptide-receptor pair has been found to have several effects including stimulation of appetite. Recently, we reported that a QRFP peptide is present in amphioxus, Branchiostoma floridae, and we also identified a QRFP receptor (QRFPR) that mediates a functional response to sub-nanomolar concentrations of the amphioxus peptide as well as short and long human QRFP (Xu et al., submitted). Because the ancestral vertebrate underwent two tetraploidizations, it might be expected that duplicates of the QRFP gene and its receptor gene may exist. Indeed, we report here the identification of multiple vertebrate QRFPR genes. Three QRFPR genes are present in the coelacanth Latimeria chalumnae, representing an early diverging sarcopterygian lineage. Three QRFPR genes are present in the basal actinopterygian fish, the spotted gar. Phylogenetic and chromosomal analyses show that only two of these receptor genes are orthologous between the two species, thus demonstrating a total of four distinct vertebrate genes. Three of the QRFPR genes resulted from the early vertebrate tetraploidizations and were copied along with syntenic neuropeptide Y receptor genes. The fourth QRFPR gene may be an even older and distinct lineage. Because mammals and birds have only a single QRFPR gene, this means that three genes have been lost in these lineages, and at least one of these was lost independently in mammals and birds because it is still present in a turtle. In conclusion, these results show that the QRFP system gained considerable complexity in the early stages of vertebrate evolution and still maintains much of this in some lineages, and that it has been secondarily reduced in mammals.

  • 34. Larsson, Marcus
    et al.
    Larhammar, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Fredrikson, Mats
    Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Granqvist, Pehr
    Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Reply to M.A. Persinger and S. A. Koren’s letter to the editor. Neuroscience Letters.2005In: Neuroscience Letters, no (i tryck)Article in journal (Other (popular scientific, debate etc.))
  • 35.
    Larsson, Tomas A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larson, Earl T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Conlon, J Michael
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Characterization of NPY receptor subtypes Y2 and Y7 in rainbow trout Oncorhynchus mykiss2006In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 6, p. 1320-1327Article in journal (Refereed)
    Abstract [en]

    We report the cloning and pharmacological characterization of two neuropeptide Y (NPY) receptor subtypes, Y2 and Y7, in rainbow trout (Oncorhynchus mykiss). These subtypes are approximately 50% identical to each other and belong to the Y2 subfamily of NPY receptors. The binding properties of the receptors were investigated after expression in human HEK-293 EBNA cells. Both receptors bound the three zebrafish peptides NPY, PYYa, and PYYb, as well as porcine NPY and PYY, with affinities in the nanomolar range that are similar to mammalian Y2. The affinity of the truncated porcine NPY fragments, NPY 13-36 and NPY 18-36 was markedly lower compared to mammalian and chicken Y2. This suggests that mammalian and chicken Y2 are unique among NPY receptors in their ability to bind truncated peptide fragments. The antagonist BIIE0246, developed for mammalian Y2, did not bind either of the two rainbow trout receptors. Our results support the proposed expansion of this gene family by duplications before the gnathostome radiation. They also reveal appreciable differences in the repertoire and characteristics of NPY receptors between fish and tetrapods stressing the importance of lineage-specific gene loss as well as sequence divergence after duplication.

  • 36.
    Larsson, Tomas A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tay, Boon-Hui
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brenner, Sydney
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Venkatesh, Byrappa
    Neuropeptide Y-family peptides and receptors in the elephant shark, Callorhinchus milii confirm gene duplications before the gnathostome radiation2009In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 93, no 3, p. 254-260Article in journal (Refereed)
    Abstract [en]

    We describe here the repertoire of neuropeptide Y (NPY) peptides and receptors in the elephant shark Callorhinchus milii, belonging to the chondrichthyans that diverged from the rest of the gnathostome (jawed vertebrate) lineage about 450 million years ago and the first chondrichthyan with a genome project. We have identified two peptide genes that are orthologous to NPY and PYY (peptide YY) in other vertebrates, and seven receptor genes orthologous to the Y1, Y2, Y4, Y5, Y6, Y7 and Y8 subtypes found in tetrapods and teleost fishes. The repertoire of peptides and receptors seems to reflect the ancestral configuration in the predecessor of all gnathostomes, whereas other lineages such as mammals and teleosts have lost one or more receptor genes or have acquired 1-2 additional peptide genes. Both the peptides and receptors showed broad and overlapping mRNA expression which may explain why some receptor gene losses could take place in some lineages, but leaves open the question why all the known ancestral receptors have been retained in the elephant shark.

  • 37.
    Larsson, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larson, Earl T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Cloning and sequence analysis of the neuropeptide Y receptors Y5 and Y6 in the coelacanth Latimeria chalumnae2007In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 150, no 2, p. 337-342Article in journal (Refereed)
    Abstract [en]

    Two coelacanth species, Latimeria chalumnae and Latimeria menadoensis, the recently discovered second species, have a key evolutionary position at the divergence of bony fishes and tetrapods. Together with lungfishes, they are the only living species separating the species-rich tetrapods from the other major group of vertebrates, the ray-finned fishes. The coelacanth is therefore of great importance for comparisons of gene families that differ between these two groups, such as the neuropeptide Y (NPY) receptor family. In this work we have sequenced the full-length genes for two NPY receptors in Latimeria chalumnae. Phylogenetic analysis indicated that the two sequences are orthologs of the mammalian Y5 and Y6 receptors. The Y5 gene has been implicated in appetite stimulation in mammals but is absent from teleost fishes. The presence of the Y5 receptor in Latimeria together with phylogenetic analysis shows that Y5 existed before the separation of bony fishes and tetrapods. The Latimeria receptor has about 62 % identity to tetrapod Y5 sequences and contains the extended third intracellular loop with several highly conserved motifs that may be involved in signal transduction. The Latimeria Y6 receptor has about 60% identity to tetrapod Y6 sequences. The functional role of Y6 is unclear as the gene is seemingly functional in some mammals but is non-functional in others. The Y6 receptor is also missing in teleost fishes. Our results confirm an early vertebrate origin for all NPY receptor subtypes presently found in mammals followed by differential gene loss in the different classes of vertebrates.

  • 38.
    Larsson, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Olsson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lundin, Lars-Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Brenner, Sydney
    Venkatesh, Byrappa
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Early vertebrate chromosome duplications and the evolution of the neuropeptide Y receptor gene regions2008In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 8, no 1, p. 184-Article, review/survey (Refereed)
    Abstract [en]

    Background

    One of the many gene families that expanded in early vertebrate evolution is the neuropeptide (NPY) receptor family of G-protein coupled receptors. Earlier work by our lab suggested that several of the NPY receptor genes found in extant vertebrates resulted from two genome duplications before the origin of jawed vertebrates (gnathostomes) and one additional genome duplication in the actinopterygian lineage, based on their location on chromosomes sharing several gene families. In this study we have investigated, in five vertebrate genomes, 45 gene families with members close to the NPY receptor genes in the compact genomes of the teleost fishes Tetraodon nigroviridis and Takifugu rubripes. These correspond to Homo sapiens chromosomes 4, 5, 8 and 10.

    Results

    Chromosome regions with conserved synteny were identified and confirmed by phylogenetic analyses in H. sapiens, M. musculus, D. rerio, T. rubripes and T. nigroviridis. 26 gene families, including the NPY receptor genes, (plus 3 described recently by other labs) showed a tree topology consistent with duplications in early vertebrate evolution and in the actinopterygian lineage, thereby supporting expansion through block duplications. Eight gene families had complications that precluded analysis (such as short sequence length or variable number of repeated domains) and another eight families did not support block duplications (because the paralogs in these families seem to have originated in another time window than the proposed genome duplication events). RT-PCR carried out with several tissues in T. rubripes revealed that all five NPY receptors were expressed in the brain and subtypes Y2, Y4 and Y8 were also expressed in peripheral organs.

    Conclusion

    We conclude that the phylogenetic analyses and chromosomal locations of these gene families support duplications of large blocks of genes or even entire chromosomes. Thus, these results are consistent with two early vertebrate tetraploidizations forming a paralogon comprising human chromosomes 4, 5, 8 and 10 and one teleost tetraploidization. The combination of positional and phylogenetic data further strengthens the identification of orthologs and paralogs in the NPY receptor family.

  • 39.
    Leprince, Jérôme
    et al.
    Normandy Univ, INSERM U1239, Lab Neuronal & Neuroendocrine Differentiat & Comm, Rouen, France.
    Bagnol, Didier
    CNS Drug Discovery, Arena Pharmaceuticals Inc., San Diego, CA, USA.
    Bureau, Ronan
    Normandy Centre for Studies and Research on Medicines (CERMN), Normandy University, Caen, France.
    Fukusumi, Shoji
    International Institute for Integrative Sleep Medicine (WPI‐IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
    Granata, Riccarda
    Laboratory of Molecular and Cellular Endocrinology, Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy .
    Hinuma, Shuji
    Department of Food and Nutrition, Faculty of Human Life Science, Senri Kinran University, Suita‐City, Osaka, Japan.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Primeaux, Stefany
    Department of Physiology, Joint Diabetes, Endocrinology & Metabolism Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
    Sopkova-de Oliveiras Santos, Jana
    Normandy Centre for Studies and Research on Medicines (CERMN), Normandy University, Caen, France.
    Tsutsui, Kazuyoshi
    Laboratory of Integrative Brain Sciences, Department of Biology, Waseda University, Center for Medical Life Science, Tokyo, Japan.
    Ukena, Kazuyoshi
    Section of Behavioral Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi‐Hiroshima, Japan.
    Vaudry, Hubert
    Normandy Univ, INSERM U1239, Lab Neuronal & Neuroendocrine Differentiat & Comm, Rouen, France.
    The Arg-Phe-amide peptide 26RFa/glutamine RF-amide peptide and its receptor: IUPHAR Review 242017In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 174, no 20, p. 3573-3607Article, review/survey (Refereed)
    Abstract [en]

    The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.

  • 40.
    Lundell, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rabe Bernhardt, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Johnsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Internalization studies of chimeric neuropeptide Y receptors Y1 and Y2 suggest complex interactions between cytoplasmic domains2011In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 168, no 1-3, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Agonist stimulation readily internalizes neuropeptide Y receptor Y1 while there are contradictory results for the Y2 receptor. In order to explore putative functional differences between the Y1 and Y2 receptors we generated reciprocal chimeras by swapping the third intracellular loop, the carboxy terminus or both between human Y1 and Y2. Internalization was studied in a quantitative radioligand binding assay with removal of surface-bound ligand in an acidic-wash procedure. The internalization assay revealed a lower degree of internalization as well as slower kinetics for the Y2 receptor. Generally, reciprocal exchange of receptor segments did not convey properties of the donor receptor but tended to enhance internalization. Surprisingly, insertion of the Y2 carboxy terminus into Y1 gave almost complete internalization (92%), rather than reduced internalization, while the insertion of both segments resulted in internalization equal to the native Y1 receptor. These findings were confirmed by fluorescence microscopy of immuno-stained receptors tagged with a C-terminal FLAG epitope. However, after exposure to high agonist concentrations (100 nM) Y2 was internalized. Studies of Y2 and the closely related Y7 receptor confirmed low internalization for Y2 from chicken and teleost fishes as well as Y7 from two teleosts. The conservation across species of low internalization at physiological concentrations suggests that this is an ancient feature and of vital importance for Y2 function. We propose that amino acid motifs in the third intracellular loop as well as the C terminus of both Y1 and Y2 are able to drive agonist-promoted internalization and that there may be constraining motifs in the Y2 receptor.

  • 41. Nylund, Karin D
    et al.
    Sjölin, Kerstin
    van der Ster, Gisela
    Larhammar, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    [Blood group diet: fantasy and quackery]2004In: Lakartidningen, ISSN 0023-7205, Vol. 101, no 41, p. 3168, 3171-2Article in journal (Other scientific)
  • 42.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evolution of the growth hormone (GH), prolactin (PRL) and somatolactin (SL) familyManuscript (preprint) (Other academic)
  • 43.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolution of the growth hormone, prolactin, prolactin 2 and somatolactin family2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 264, p. 94-112Article in journal (Refereed)
    Abstract [en]

    Growth hormone (GH), prolactin (PRL), prolactin 2 (PRL2) and somatolactin (SL) belong to the same hormone family and have a wide repertoire of effects including development, osmoregulation, metabolism and stimulation of growth. Both the hormone and the receptor family have been proposed to have expanded by gene duplications in early vertebrate evolution. A key question is how hormone-receptor preferences have arisen among the duplicates. The first step to address this is to determine the time window for these duplications. Specifically, we aimed to see if duplications resulted from the two basal vertebrate tetraploidizations (1R and 2R). GH family genes from a broad range of vertebrate genomes were investigated using a combination of sequence-based phylogenetic analyses and comparisons of synteny. We conclude that the PRL and PRL2 genes arose from a common ancestor in 1R/2R, as shown by neighboring gene families. No other gene duplicates were preserved from these tetraploidization events. The ancestral genes that would give rise to GH and PRL/PRL2 arose from an earlier duplication; most likely a local gene duplication as they are syntenic in several species. Likewise, some evidence suggests that SL arose from a local duplication of an ancestral GH/SL gene in the same time window, explaining the lack of similarity in chromosomal neighbors to GH, PRL or PRL2. Thus, the basic triplet of ancestral GH, PRL/ PRL2 and SL genes appear to be unexpectedly ancient. Following 1R/2R, only SL was duplicated in the teleost-specific tetraploidization 3R, resulting in SLa and SLb. These time windows contrast with our recent report that the corresponding receptor genes GHR and PRLR arose through a local duplication in jawed vertebrates and that both receptor genes duplicated further in 3R, which reveals a surprising asynchrony in hormone and receptor gene duplications.

  • 44.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evolution of the receptors for growth hormone, prolactin, erythropoietin and thrombopoietin in relation to the vertebrate tetraploidizations2018In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 257, p. 143-160Article in journal (Refereed)
    Abstract [en]

    The receptors for the pituitary hormones growth hormone (GH), prolactin (PRL) and somatolactin (SL), and the hematopoietic hormones erythropoietin (EPO) and thrombopoietin (TPO), comprise a structurally related family in the superfamily of cytokine class-I receptors. GH, PRL and SL receptors have a wide variety of effects in development, osmoregulation, metabolism and stimulation of growth, while EPO and TPO receptors guide the production and differentiation of erythrocytes and thrombocytes, respectively. The evolution of the receptors for GH, PRL and SL has been partially investigated by previous reports suggesting different time points for the hormone and receptor gene duplications. This raises questions about how hormone-receptor partnerships have emerged and evolved. Therefore, we have investigated in detail the expansion of this receptor family, especially in relation to the basal vertebrate (1R, 2R) and teleost (3R) tetraploidizations. Receptor family genes were identified in a broad range of vertebrate genomes and investigated using a combination of sequence-based phylogenetic analyses and comparative genomic analyses of synteny. We found that 1R most likely generated EPOR/TPOR and GHR/PRLR ancestors; following this, 2R resulted in EPOR and TPOR genes. No GHR/PRLR duplicate seems to have survived after 2R. Instead the single GHR/PRLR underwent a local duplication sometime after 2R, generating separate syntenic genes for GHR and PRLR. Subsequently, 3R duplicated the gene pair in teleosts, resulting in two GHR and two PRLR genes, but no EPOR or TPOR duplicates. These analyses help illuminate the evolution of the regulatory mechanisms for somatic growth, metabolism, osmoregulation and hematopoiesis in vertebrates.

  • 45.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The growth hormone receptor (GHR) and prolactin receptor (PRLR) gene family expanded in the basal teleost tetraploidizationManuscript (preprint) (Other academic)
  • 46.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lewicka, Michalina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The oxytocin/vasopressin receptor family has at least five members in the gnathostome lineage, inclucing two distinct V2 subtypes2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 135-143Article in journal (Refereed)
    Abstract [en]

    The vertebrate oxytocin and vasopressin receptors form a family of G-protein-coupled receptors (GPCRs) that mediate a large variety of functions, including social behavior and the regulation of blood pressure, water balance and reproduction. In mammals four family members have been identified, three of which respond to vasopressin (VP) named V1A, V1B and V2, and one of which is activated by oxytocin (OT), called the OT receptor. Four receptors have been identified in chicken as well, but these have received different names. Until recently only V1-type receptors have been described in several species of teleost fishes. We have identified family members in several gnathostome genomes and performed phylogenetic analyses to classify OT/VP-receptors across species and determine orthology relationships. Our phylogenetic tree identifies five distinct ancestral gnathostome receptor subtypes in the OT/VP receptor family: V1A, V1B, V2A, V2B and OT receptors. The existence of distinct V2A and V2B receptors has not been previously recognized. We have found these two subtypes in all examined teleost genomes as well as in available frog and lizard genomes and conclude that the V2A-type is orthologous to mammalian V2 receptors whereas the V2B-type is orthologous to avian V2 receptors. Some teleost fishes have acquired additional and more recent gene duplicates with up to eight receptor family members. Thus, this analysis reveals an unprecedented complexity in the gnathostome repertoire of OT/VP receptors, opening interesting research avenues regarding functions such as regulation of water balance, reproduction and behavior, particularly in reptiles, amphibians, teleost fishes and cartilaginous fishes.

  • 47.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergqvist, Christina A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Duan, Cunming
    Dept of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Evolution of the insulin-like growth factor binding protein (IGFBP) family2011In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 152, no 6, p. 2278-2289Article in journal (Refereed)
    Abstract [en]

    The evolution of the insulin-like growth factor binding protein  (IGFBP) gene family has been difficult to resolve. The early discovery of IGFBP gene synteny with the HOX (homeobox) gene clusters suggested that IGFBP was quadrupled along with HOX in the ancestral vertebrate chromosome duplications. However, some recent articles have favored independent serial duplications of the IGFBP genes. By combining sequence-based phylogenies and chromosome information from multiple vertebrate species, we conclude that chromosome duplications did indeed expand the IGFBP repertoire. After the ancestral chordate IGFBP gene had undergone a local gene duplication, resulting in a gene pair adjacent to a HOX cluster, chromosome quadruplication of this pair took place in the two basal vertebrate tetraploidizations (2R). Subsequently one gene was lost from two of the four pairs, leading to six IGFBP genes in the fish-tetrapod ancestor. These six genes are presently found in placental mammals. In teleost fishes the situation is more complex: their third tetraploidization (3R) doubled the IGFBP repertoire from six to twelve members whereupon differential losses have occurred. The five sequenced teleost fish genomes retain 9-11 of IGFBP genes. This scenario is supported by the phylogenies of three adjacent gene families, namely the epidermal growth factor receptors (EGFR) and the Ikaros and distal-less (Dlx) transcription factors, in addition to the HOX clusters. The great ages for the IGFBP genes strongly suggest that they evolved distinct functions early in vertebrate evolution.

  • 48.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Bergqvist, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    The evolution of vertebrate somatostatin receptors and their gene regions involves extensive chromosomal rearrangements.2012In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 12, p. 231-Article in journal (Refereed)
    Abstract [en]

    Background: Somatostatin and its related neuroendocrine peptides have a wide varietyof physiological functions that are mediated by five somatostatin receptors with gene names SSTR1-5 in mammals. To resolve their evolution in vertebrates we have investigated the SSTR genes and a large number of adjacent gene families by phylogeny and conserved synteny analyses in a broad range of vertebrate species. Results: We find that the SSTRs form two families that belong to distinct paralogons. We observe not only chromosomal similarities reflecting the paralogy relationships between the SSTR-bearing chromosome regions, but also extensive rearrangements between these regions in teleost fish genomes, including fusions and translocations followed by reshuffling through intrachromosomalrearrangements. These events obscure the paralogy relationships but are still tractable thanks tothe many genomes now available. We have identified a previously unrecognized SSTR subtype, SSTR6, previously misidentified as either SSTR1 or SSTR4. Conclusions: Two ancestral SSTR-bearing chromosome regions were duplicated in the two basalvertebrate tetraploidizations (2R). One of these ancestral SSTR genes generated SSTR2, -3 and -5, the other gave rise to SSTR1, -4 and -6. Subsequently SSTR6 was lost in tetrapods and SSTR4 in teleosts. Our study shows that extensive chromosomal rearrangements have taken place between related chromosome regions in teleosts, but that these events can be resolved by investigating several distantly related species.

  • 49.
    Pedersen, Julia E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bergqvist, Christina A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolution of the muscarinic acetylcholine receptors in vertebratesManuscript (preprint) (Other academic)
  • 50.
    Pedersen, Julia E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evolution of the muscarinic acetylcholine receptors in vertebrates2018In: eNeuro, ISSN 2373-2822, Vol. 5, no 5, article id UNSP e0340-18.2018Article in journal (Refereed)
    Abstract [en]

    The family of muscarinic acetylcholine receptors (mAChRs) consists of five members in mammals, encoded by theCHRM1-5 genes. The mAChRs are G-protein-coupled receptors, which can be divided into the following two subfamilies: M2 and M4 receptors coupling to Gi/o; and M1, M3, and M5 receptors coupling to Gq/11. However, despite the fundamental roles played by these receptors, their evolution in vertebrates has not yet been fully described. We have combined sequence-based phylogenetic analyses with comparisons of exon–intron organi- zation and conserved synteny in order to deduce the evolution of the mAChR receptors. Our analyses verify the existence of two ancestral genes prior to the two vertebrate tetraploidizations (1R and 2R). After these events, one gene had duplicated, resulting in CHRM2 and CHRM4; and the other had triplicated, forming the CHRM1,CHRM3, and CHRM5 subfamily. All five genes are still present in all vertebrate groups investigated except theCHRM1 gene, which has not been identified in some of the teleosts or in chicken or any other birds. Interestingly, the third tetraploidization (3R) that took place in the teleost predecessor resulted in duplicates of all five mAChR genes of which all 10 are present in zebrafish. One of the copies of the CHRM2 and CHRM3 genes and bothCHRM4 copies have gained introns in teleosts. Not a single separate (nontetraploidization) duplicate has been identified in any vertebrate species. These results clarify the evolution of the vertebrate mAChR family and reveal a doubled repertoire in zebrafish, inviting studies of gene neofunctionalization and subfunctionalization.

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