or 
Receptor Family
7TM | A | Polypeptide    Apelin/angiotensin/bradykinin
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(Summary from Seven transmembrane (7TM) receptors)

These proteins of ancient origin that first emerged in unicellular organisms have seven discrete and highly predictable transmembrane domains (6). The central role of the 7TM guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) in multicellular organisms is reflected by their diversity (7). Ligand occupancy of GPCRs induces a conformational change in the receptor that recruits and activates diverse G proteins, which stimulate the generation of adenosine 3',5'-monophosphate (cAMP), phosphoinositides, diacylglycerol, and other second messengers. This, in turn, triggers such events as activation of kinase cascades and phosphorylation of cytosolic factors and nuclear transcriptional factors (8). Activated GPCRs also recruit GPCR receptor kinases (GRKs) that phosphorylate the receptors themselves to facilitate termination of signaling or receptor turnover. The extracellular stimuli that activate 7TM receptors include light, simple ions, odorants, nucleotides, lipids, steroids, modified amino acids, peptides, and glycoprotein hormones. They are the only non-channel plasma membrane receptors that are activated by inorganic chemicals and physical stimuli. Although the dimerization of most 7TM receptors is not essential for their function (7), some receptors [for example the gamma-amino butyric acid (GABA) receptors] require heterodimerization of paralogs for their proper expression and function (9). Dictyostelium discoideum can exist as either single-celled organisms or as a colony of social amoebas. In this eukaryotic organism, folate-sensing and cAMP-sensing are mediated by two different 7TM receptors (10). This dichotomy may represent the earliest divergence between detecting ligands of foreign origin (folate) and ligands produced within the multicellular organism itself (cAMP). Sequence similarities of 7TM receptors, stemming from phylogenetic relatedness, are confined largely to the transmembrane domains (11). The current classification of human 7TM receptors includes four defined classes (A, B, C, and Frizzled) and the olfactory receptor families (http://www.gpcr.org/7tm/phylo/phylo.html)(12). Each class of GPCRs shows substantial differences in their transmembrane sequences and can not be traced to a single evolutionary origin. The yeast Saccharomyces cerevisiae contains only two unique classes of GPCR (pheromone and glucose receptors), whereas the metazoans have developed different subtypes of 7TM receptors. When compared with invertebrates, major expansion of class A GPCRs is evident in vertebrates. In the olfactory receptor family, there are many odorant and gustatory GPCRs in nematodes and mammals (human: 400; mouse: 1,200; worm: 800), but fewer numbers of them are present in teleosts and insects, likely representing adaptation to their unique environments and the acquisition of lineage-specific functions. An evolutionary genomic re-evaluation of the GPCR superfamily could more fully reveal the structure-function relationships of these proteins. This approach could facilitate the discovery of drugs for pharmacological intervention (13), as well as the search for ligands for a still large group of orphan 7TM receptors (14). The Drosophila melanogaster 7TM receptor Frizzled is a unique member of the 7TM receptor superfamily because receptor activity is modulated by interactions with additional plasma membrane receptors. Ligand activation of the Frizzled receptor by Wingless (Wnt) (15) culminates in the accumulation of beta-catenin, which, in turn, modulates gene transcription. Signal transduction by Frizzled receptors requires the participation of a low density lipoprotein (LDL) receptor-related protein, LRP5 or LRP6 (16). LRP5 and LRP6 themselves bind a ligand named Dikkopf1 (Dkk1), which inhibits Wnt signaling. Dkk1 also binds two other transmembrane receptors (Kremen1 and Kremen2), which stimulates endocytosis of the LRPs thereby further modulating the Wnt signaling (17). Although G protein coupling is not its main signaling mechanism, Frizzled receptors may interact with G proteins in some contexts (18).
Relevant reviews and publications:
6. M. J. Marinissen, J. S. Gutkind, G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22, 368-376 (2001). 7. K. L. Pierce, R. T. Premont, R. J. Lefkowitz, Signalling: Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3, 639-650 (2002). 8. A. H. Brivanlou, J. E. Darnell, Jr., Signal transduction and the control of gene expression. Science 295, 813-818 (2002). 9. J. H. White, A. Wise, M. J. Main, A. Green, N. J. Fraser, G. H. Disney, A. A. Barnes, P. Emson, S. M. Foord, F. H. Marshall, Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 396, 679-682 (1998). 10. R. L. Johnson, C. L. Saxe, 3rd, R. Gollop, A. R. Kimmel, P. N. Devreotes, Identification and targeted gene disruption of cAR3, a cAMP receptor subtype expressed during multicellular stages of Dictyostelium development. Genes Dev 7, 273-282 (1993). 11. J. M. Otaki, S. Firestein, Length analyses of mammalian G-protein-coupled receptors. J Theor Biol 211, 77-100 (2001). 12. D. K. Vassilatis, J. G. Hohmann, H. Zeng, F. Li, J. E. Ranchalis, M. T. Mortrud, A. Brown, S. S. Rodriguez, J. R. Weller, A. C. Wright, et al., The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A 100, 4903-4908 (2003). 13. M. Sautel, G. Milligan, Molecular manipulation of G-protein-coupled receptors: a new avenue into drug discovery. Curr Med Chem 7, 889-896 (2000). 14. A. D. Howard, G. McAllister, S. D. Feighner, Q. Liu, R. P. Nargund, L. H. Van der Ploeg, A. A. Patchett, Orphan G-protein-coupled receptors and natural ligand discovery. Trends Pharmacol Sci 22, 132-140 (2001). 15. C. E. Dann, J. C. Hsieh, A. Rattner, D. Sharma, J. Nathans, D. J. Leahy, Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86-90 (2001). 16. K. I. Pinson, J. Brennan, S. Monkley, B. J. Avery, W. C. Skarnes, An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535-538 (2000). 17. B. Mao, W. Wu, G. Davidson, J. Marhold, M. Li, B. M. Mechler, H. Delius, D. Hoppe, P. Stannek, C. Walter, et al., Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417, 664-667 (2002). 18. R. Winklbauer, A. Medina, R. K. Swain, H. Steinbeisser, Frizzled-7 signalling controls tissue separation during Xenopus gastrulation. Nature 413, 856-860 (2001).
no tree for this subfamily