Melanocortin 5 receptor (Melancort_rcpt_5)
Type: Family

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 . 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 . 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) . 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 . 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 .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) and beta-endorphin are peptide products of pituitary pro-opiomelanocortin. ACTH regulates synthesis and release of glucocorticoids and aldosterone in the adrenal cortex; it also has a trophic action on these cells. ACTH and beta-endorphin are synthesised and released in response to corticotrophin-releasing factor at times of stress (heat, cold, infections, etc.) - their release leads to increased metabolism and analgesia. MSH has a trophic action on melanocytes, and regulates pigment production in fish and amphibia. The ACTH receptor is found in high levels in the adrenal cortex - binding sites are present in lower levels in the CNS. The MSH receptor is expressed in high levels in melanocytes, melanomas and their derived cell lines. Receptors are found in low levels in the CNS. MSH regulates temperature control in the septal region of the brain and releases prolactin from the pituitary.

A further gene, which encodes a melanocortin receptor that is functionally distinct from the ACTH and MSH receptors, has also been characterised . The protein contains ~300 amino acids, with calculated molecular mass of ~36kDa, and potential N-linked glycosylation and phosphorylation sites . The melanocortin 5 receptor (MC5-R) mediates increase in cAMP accumulation with a characteristic pharmacology . Very low expression levels have been detected in brain, while high levels are found in adrenals, stomach, lung and spleen . In situ hybridisation studies have also shown the MC5 receptor to be expressed in the three layers of the adrenal cortex, predominantly in the aldosterone-producing zona glomerulosa cells . Structure-activity studies have indicated that N- and C-terminal portions of alpha-MSH appear to be key determinants in the activation of mouse MC5R, while the melanocortin core heptapeptide sequence is devoid of pharmacological activity .