Melanocortin 4 receptor (Mcort_rcpt_4)
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 4 receptor (MC4-R) is regulated by opiate administration . Rat MC4-R is 95% identical to human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologues . Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates (and are regions in which MC1-, MC3- and MC5-R are expressed at low or undetectable levels) . MC4-R mRNA has been found in multiple sites in virtually every brain region, including the cortex, thalamus, hypothalamus, brainstem, and spinal cord . Unlike the MC3-R, MC4-R mRNA is found in both parvicellular and magnocellular neurons of the paraventricular nucleus of the hypothalamus, suggesting a role in the central control of pituitary function .