GPCR, family 3, extracellular calcium-sensing receptor-related (IPR000068)

Short name: GPCR_3_Ca_sens_rcpt-rel

Overlapping homologous superfamilies

Family relationships



G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups [PMID: 12679517]. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [PMID: 8170923]. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [PMID: 8170923, PMID: 8081729, PMID: 15914470, PMID: 18948278, PMID: 16753280]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice [PMID: 12679517]. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [PMID: 23020293].

The metabotropic glutamate receptors are functionally and pharmacologically distinct from the ionotropic glutamate receptors. They are coupled to G-proteins and stimulate the inositol phosphate/Ca2+ intracellular signalling pathway [PMID: 1847995, PMID: 1656524, PMID: 1320017, PMID: 1309649]. At least eight sub-types of metabotropic receptor (MGR1-8) have been identified in cloning studies. The sub-types differ in their agonist pharmacology and signal transduction pathways.

The calcium-sensing receptor (CaSR) is an integral membrane protein that senses changes in the extracellular concentration of calcium ions. The activity of the receptor is mediated by a G-protein that activates a phosphatidyl-inositol-calcium second messenger system. The sequences of the receptors show a high degree of similarity to the TM signature that characterises the metabotropic glutamate receptors. In addition, the sequences contain a large extracellular domain that includes clusters of acidic amino acid residues, which may be involved in calcium binding [PMID: 8255296]. Defects in CaSR that result in reduced activity of the receptor cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), inherited conditions characterised by altered calcium homeostasis [PMID: 9298824, PMID: 8675635]. FHH-affected individuals exhibit mild or modest hypercalcemia, relative hypocalciuria and inappropriately normal PTH levels. By contrast, NSHPT is a rare autosomal recessive life-threatening disorder characterised by high serum calcium concentrations, skeletal demineralisation and parathyroid hyperplasia. In addition, defects resulting from receptor activation at subnormal Ca2+ levels cause autosomal dominant hypocalcemia [PMID: 7874174].

This entry represents the extracellular calcium-sensing receptors and related proteins in GPCR family 3, such as the taste receptors.

GO terms

Biological Process

GO:0007186 G protein-coupled receptor signaling pathway

Molecular Function

GO:0004930 G protein-coupled receptor activity

Cellular Component

GO:0016021 integral component of membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.