Abcdef Classification of GPCRs

The conventional classification of the GPCR superfamily into six families (A-F) is maintained at the primary GPCR resource (GPCRDB,, which has moved to the University of Nijmegen, The Netherlands, with its cofounder Gerrit Vriend. The American "mirror" GPCRDB4 has suffered the fate of so many comprehensive scientific databases and has been privatized. The 7TMRs and GPCRs are assigned to class 2 in the IUPHAR receptor database (, with individual receptors encoded in a manner similar to the EC nomenclature for enzymes (or even IP addresses), with individual receptor subcommittees publishing definitive reports in Pharmacological Reviews.

The A-F classification system is derived from a combination of multiple sequence alignment (MSA), endogenous ligand specificity, and species source. The two largest families are A and B. Family A includes rhodopsin-related members and is dominated by the biogenic amine receptors and many peptide hormones. Family B includes the remainder of the peptide hormones. Family C has a few receptors of the metabotropic glutamate type, whereas families D and E are pheromone receptors only to be found in yeasts; family F receptors are Dictyostelium cAMP receptors.

Rhodopsin is an undisputed member of the family A receptors and is also the best studied, truly archetypical GPCR. Visual transduction is mediated by activation and dissociation of both chromophore and G protein from the opsin, releasing the opsin constitutive activity which is desensitized and downregulated by specific phosphorylation. Thus, the dark-adapted form of rhodopsin with its covalently attached chromophore can be considered an inverse agonist or antagonist-blocked, constrained and inactive form of a constitutively active receptor.

Human GPCRs are of the family ABC types, although a diverse set of 7TM-like sequences related to the developmental products of the BOSS and frizzled genes in Drosophila are now included in the 7TMR superfamily. BOSS has a 500-amino acid amino-terminal domain that interacts with the sevenless gene-encoded receptor tyrosine kinase5 and retains the characteristic disulfide bridge between the extracellular loops 1 and 2. The BOSS 7TMR and the sevenless RTK "ligand" coordinate development of the retinal photoreceptors of the fly ommatidia, with photoreceptor cells arranged in a group of seven around a central coordinator.

Family C metabotropic receptors are distinguished by huge amino and carboxyl acquisitions, whereas families A and B include some subfamilies with large extracellular extensions. Family A has the most representatives and interacts with the broadest range of ligands, from the opsins responsible for visual perception and the olfactory and some gustatory receptors responsible for smell and taste, to the receptors for monoamine, nucleotide, lipid, peptide and protein hormones, many chemokines, and the enzyme thrombin. Generally, family A 7TMRs are presumed to adopt the folding topology of rhodopsin, with a common 7TM core, extracellular amino and intracellular carboxyl termini, and a presumed dithiol bridge between the extracellular loops 1 and 2. For some of the receptors, TM1 can be the uncleaved signal peptide of the protein sequence and the extracellular sequences are generally glycosylated.

The great diversity in family A receptors has produced many attempts at classification that are almost as diverse in their results. Classification can be according to DNA or primary sequence, by structure of amino and carboxyl acquisitions, by protein-complex associations, by ligand, or by function (which necessarily is a combination of the above), such as olfactory or endocrine, or by pathology, such as mutations causing inactivity or constitutive activation and exogenous 7TMRs encoded and expressed by an infecting virus.

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