GPCR, family 2, corticotropin releasing factor receptor, type 2 (IPR003053)

Short name: GPCR_2_CRF2_rcpt

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 secretin-like GPCRs include secretin [PMID: 1646711], calcitonin [PMID: 1658940], parathyroid hormone/parathyroid hormone-related peptides [PMID: 1658941] and vasoactive intestinal peptide [PMID: 1314625], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N terminus is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allow the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

Corticotropin-releasing factor (CRF) is the principal neuroregulator of the hypothalamic-pituitary-adrenocortical axis, playing an important role in coordinating the endocrine, autonomic and behavioral responses to stress and immune challenge [PMID: 7692441]. The CRF receptor has been found in human cortex tissue, pituitary, brainstem and testis [PMID: 8243652]. The protein comprises 415 amino acid residues with the characterstic 7TM architecture of the secretin-like GPCR superfamily. Three isoforms (designated CRF-R1, CRF-R2 and CRF-R3) are produced as a result of alternative splicing of the same gene: CRF-R1 appears to be the predominant form; CRF-R3 does not bind to CRF with a high affinity [PMID: 7692441].

For the CRF-R2 receptor, at least 2 splice forms with different 5'-coding sequences (CRF2 alpha and CRF2 beta) have been identified in rat [PMID: 8536644]. The sequence of the CRF-R is highly conserved between species, the majority of the sequence divergence occuring in the putative signal peptide and extracellular N-terminal domain. The relative abundance of CRF-R2 messenger RNA appears to be lower in humans than in rats for the heart and skeletal tissues studied to date [PMID: 8536644]. CRF-R2 stimulates cAMP production in response to CRF and known CRF-like agonists [PMID: 7846062]. CRF and the non-mammalian CRF-related peptides sauvagine and urotensin I stimulate adenylate cyclase activity in a dose-dependent manner, with a rank order of potency that differs from that of the CRF1 receptor (sauvagine>urotensin>=rat/human CRF>ovine CRF). The differences in the pharmacological profiles and tissue distributions of CRF-R1 and CRF-R2 suggests important functional differences between the two receptors [PMID: 7846062].

GO terms

Biological Process

No terms assigned in this category.

Molecular Function

GO:0004930 G protein-coupled receptor activity

Cellular Component

GO:0016020 membrane

Contributing signatures

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