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Origin of the prolactin-releasing hormone (PRLH) receptors: Evidence of coevolution between PRLH and a redundant neuropeptide Y receptor during vertebrate evolution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Farmakologi 3)
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2005 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 85, no 6, 688-703 p.Article in journal (Refereed) Published
Abstract [en]

We present seven new vertebrate homologs of the prolactin-releasing hormone receptor (PRLHR) and show that these are found as two separate subtypes, PRLHR1 and PRLHR2. Analysis of a number of vertebrate sequences using phylogeny, pharmacology, and paralogon analysis indicates that the PRLHRs are likely to share a common ancestry with the neuropeptide Y (NPY) receptors. Moreover, a micromolar level of NPY was able to bind and inhibit completely the PRLH-evoked response in PRLHR1-expressing cells. We suggest that an ancestral PRLH peptide started coevolving with a redundant NPY binding receptor, which then became PRLHR, approximately 500 million years ago. The PRLHR1 subtype was shown to have a relatively high evolutionary rate compared to receptors with fixed peptide preference, which could indicate a drastic change in binding preference, thus supporting this hypothesis. This report suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions.

Place, publisher, year, edition, pages
2005. Vol. 85, no 6, 688-703 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94034DOI: 10.1016/j.ygeno.2005.02.007PubMedID: 15885496OAI: oai:DiVA.org:uu-94034DiVA: diva2:167725
Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2013-04-04Bibliographically approved
In thesis
1. Classification, Evolution, Pharmacology and Structure of G protein-coupled Receptors
Open this publication in new window or tab >>Classification, Evolution, Pharmacology and Structure of G protein-coupled Receptors
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

G protein-coupled receptors (GPCR) are integral membrane proteins with seven α-helices that translate a remarkable diversity of signals into cellular responses. The superfamily of GPCRs is among the largest and most diverse protein families in vertebrates.

We have searched the human genome for GPCRs and show that the family includes approximately 800 proteins, which can divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin. This study represents one of the first overall road maps of the GPCR family in a mammalian genome. Moreover, we identified eight novel members of the human Adhesion family which are characterized by long N-termini with various domains. We also investigated the GPCR repertoire of the chicken genome, where we manually verified a total of 557 chicken GPCRs. We detected several specific expansions and deletions that may reflect some of the functional differences between human and chicken.

Substantial effort has been made over the years to find compounds that can bind and activate the melanocortin 4 receptor (MC4R). This receptor is involved in food intake and is thus an important target for antiobesity drugs. We used site-directed mutagenesis to insert micromolar affinity binding sites for zinc between transmembrane (TM) regions 2 and 3. We generated a molecular model of the human MC4R which suggests that a rotation of TM3 is important for activation of the MC4R.

Furthermore, we present seven new vertebrate prolactin releasing hormone receptors (PRLHRs) and show that they form two separate subtypes, PRLHR1 and PRLHR2. We performed a pharmacological characterization of the human PRLHR which showed that the receptor can bind neuropeptide Y (NPY) related ligands. We propose that an ancestral PRLH peptide has coevolved with a redundant NPY binding receptor, which then became PRLHR. This suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 108
Keyword
Pharmacology, Classification, Structure, Pharmacology, Evolution, G protein-coupled receptor, Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-6356 (URN)91-554-6466-1 (ISBN)
Public defence
2006-03-24, Room B21, BMC, Husargatan 3, Uppsala, 09:15
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Supervisors
Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2013-04-04Bibliographically approved

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Lagerström, Malin C.

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