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G-Protein Coupled Receptors

All G-protein-coupled receptors (GPCRs) share a common molecular architecture (with seven putative transmembrane segments) and a common signaling mechanism, in that they interact with G proteins (heterotrimeric GTPases) to regulate the synthesis of intracellular second messengers such as cyclic AMP, inositol phosphates, diacylglycerol and calcium ions. Historically, GPCRs have been classified into six families,

which were thought to be unrelated; three of these are found in vertebrates. Recent work has identified several new GCPR families and suggested the possibility of a common evolutionary origin for all of them. Family B (the secretin-receptor family or 'family 2') of the GPCRs is a small but structurally and functionally diverse group of proteins that includes receptors for polypeptide hormones, molecules thought to mediate intercellular interactions at the plasma membrane and a group of Drosophila proteins that regulate stress responses and longevity. Family-B GPCRs have been found in all animal species investigated, including mammals, Caenorhabditis elegans and Drosophila melanogaster, but not in plants, fungi or prokaryotes. In this article, I describe the structures and functions of family-B GPCRs and propose a simplified nomenclature for these proteins.

 

All G-protein-coupled receptors (GPCRs) are thought to have the same molecular architecture, consisting of seven transmembrane domains (7TM), three extracellular loops (EC1, EC2, EC3), three intracellular loops (IC1, IC2, and IC3), an amino-terminal extracellular domain and an intracellular carboxyl terminus. This topology is predicted from the analysis of hydropathy profiles and from a limited amount of experimental evidence, most importantly from the crystal structure of the visual pigment rhodopsin, a GPCR for which the activating stimulus is light. GPCRs were classified by Kolakowski into six families: the rhodopsin family (A), the secretin-receptor family (B), the metabotropic glutamate receptor family (C), fungal pheromone P- and α-factor receptors (D), fungal pheromone A- and M-factor receptors (E) and cyclic-AMP receptors from Dictyostelium (F). Note that families A-C are named after well-known members and contain other members that are not rhodopsins, secretin receptors or metabotropic glutamate receptors, respectively. The 7TM topology was thought to have evolved independently in each family, representing a "remarkable example of a molecular convergence". More recent work has identified several new families of putative GPCRs and provided evidence that some or all of these proteins may have a common evolutionary origin. Josefsson analyzed distant sequence homologies between GPCR families and suggested that the GPCRs fall into three superfamilies. Graul and Sadée confirmed and extended this analysis to propose a common evolutionary origin for most of the known GPCRs. In 1991, Nagata's group reported the expression cloning of the receptor for the gut hormone secretin. The secretin receptor was predicted to have the 7TM topology characteristic of GPCRs and was capable of regulating intracellular concentrations of cyclic AMP by coupling to adenylate cyclase. But the amino-acid sequence of the protein was only very distantly homologous to that of other known GPCRs and the secretin receptor became, thus, the prototype member of family B.


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