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There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini
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 Neuroscience, Pharmacology.
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 Neuroscience.
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2003 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 301, no 3, 752-734 p.Article in journal (Refereed) Published
Abstract [en]

We report six novel members of the superfamily of human G-protein coupled receptors (GPCRs) found by searches in the human genome databases, termed GPR123, GPR124, GPR125, GPR126, GPR127, and GPR128. Phylogenetic analysis demonstrates that these are additional members of the family of GPCRs with long N-termini, previously termed EGF-7TM, LNB-7TM, B2 or LN-7TM, showing that there exist at least 30 such GPCRs in the human genome. Three of these receptors form their own phylogenetic cluster, while two other places in a cluster with the previously reported HE6 and GPR56 (TM7XN1) and one with EMR1-3. All the novel receptors have a GPS domain in their N-terminus, except GPR123, as well as long Ser/Thr rich regions forming mucin-like stalks. GPR124 and GPR125 have a leucine rich repeat (LRR), an immunoglobulin (Ig) domain, and a hormone-binding domain (HBD). The Ig domain shows similarities to motilin and titin, while the LRR domain shows similarities to LRIG1 and SLIT1-2. GPR127 has one EGF domain while GPR126 and GPR128 do not contain domains that are readily recognized in other proteins beyond the GPS domain. We found several human EST sequences for most of the receptors showing differential expression patterns, which may indicate that some of these receptors participate in central functions while others are more likely to have a role in the immune or reproductive systems.

Place, publisher, year, edition, pages
2003. Vol. 301, no 3, 752-734 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94262DOI: 10.1016/S0006-291X(03)00026-3PubMedID: 12565841OAI: oai:DiVA.org:uu-94262DiVA: diva2:168052
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
In thesis
1. G Protein-Coupled Receptors; Discovery of New Human Members and Analyses of the Entire Repertoires in Human, Mouse and Rat
Open this publication in new window or tab >>G Protein-Coupled Receptors; Discovery of New Human Members and Analyses of the Entire Repertoires in Human, Mouse and Rat
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

G protein-coupled receptors (GPCRs) are signal mediators that have a prominent role in the regulation of physiological processes and they make up the targets for 30-45% of all drugs.

Papers I and II describe the discovery of new human GPCRs belonging to the Rhodopsin family, a family which contains many common drug targets. The new receptors have only weak relationships to previously known GPCRs. However, they have been evolutionary conserved in several species and most of them display distinct expression patterns.

In paper III we identified new human GPCRs belonging to the Adhesion family, which is characterised by very long N-termini containing conserved domains. The different compositions of conserved domains as well as the expression patterns suggest that the Adhesions can have several different functions.

In paper IV we revealed remarkable species variations in the repertoires of Trace Amine-Associated Receptors (TAARs), which are relatives of the biogenic amine receptors. The human, mouse and rat TAAR genes are located in only one locus and are therefore most likely the result of gene tandem duplications. 47 of the 57 zebrafish TAARs were mapped to nine different loci on six chromosomes containing from 1 to 27 genes each. This study suggests that the TAARs arose through several different mechanisms involving tetraploidisation, block duplications, and local duplication events.

Papers V and VI are overall analyses of the repertoires of GPCRs in humans, mice and rats; which contain approximately 800, 1800 and 1900 members, respectively. The repertoires were compared to distinguish between species-specific and common (orthologous) members, something which is important for example when predicting drug effects from experiments in rodents. The Glutamate, Adhesion, Frizzled and Secretin families show no or very little variation between human and rodents, whereas the repertoires of olfactory, vomeronasal and Taste2 receptors display large differences between all three species.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 133
Keyword
Bioinformatics, G protein-coupled receptor, GPCR, Bioinformatics, Evolution, Orphan, Rhodopsin, Adhesion, Phylogeny, Bioinformatik
Identifiers
urn:nbn:se:uu:diva-6745 (URN)91-554-6522-6 (ISBN)
Public defence
2006-04-28, Room B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2011-06-17Bibliographically approved
2. Identification, Characterization and Evolution of Membrane-bound Proteins
Open this publication in new window or tab >>Identification, Characterization and Evolution of Membrane-bound Proteins
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane proteins constitute approximately 30% of all genes in the human genome and two large families of membrane proteins are G protein-coupled receptors (GPCRs) and Solute Carriers (SLCs) with about 800 and 380 human genes, respectively.

In Papers I, II and IV, we report 16 novel human Adhesion GPCRs found by searches in NCBI and Celera databases. In Paper I, we report eight novel human GPCRs, and six in Paper II. We identified two new human Adhesion GPCRs and 17 mouse orthologs in Paper IV. Phylogenetic analysis demonstrates that the 16 novel human genes are additional members of the Adhesion GPCR family and can be divided into eight phylogenetic groups. EST expression charts for the entire repertoire of Adhesions in human and mouse were established, showing widespread distribution in both central and peripheral tissues. Different domains were found in their N-terminus, some, such as pentraxin in GPR112, indicates that they take part in immunological processes.

In Paper III, we discovered seven new human Rhodopsin GPCRs.

In Paper V, we present the identification of two new human genes, termed SLC6A17 and SLC6A18 from the Solute Carriers family 6 (SLC6). We also identified the corresponding orthologs and additional genes from the mouse and rat genomes. We analysed, in total, 430 unique SLC6 proteins from 10 animal, one plant, two fungi and 196 bacterial genomes.

In Paper VI, we provide the first systematic analysis of the evolutionary history of the different SLC families in Eukaryotes. In all, we analysed 2403 sequences in eight species and we delineate the evolutionary history of each of the 46 SLC families.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 388
Keyword
G protein-coupled receptor, GPCR, Solute Carriers, SLC, Bioinformatics, Evolution, Rhodopsin, Adhesion, Phylogeny
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-9329 (URN)978-91-554-7312-9 (ISBN)
Public defence
2008-11-15, Room B21, BMC, Husargatan 3, Uppsala, 09:00
Opponent
Supervisors
Available from: 2008-10-23 Created: 2008-10-23 Last updated: 2013-04-04Bibliographically approved

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