Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA

Abstract

Melanoeytes and melanoma cells are known to possess receptors for melanoeyte stimulating hormone (MSH). A eDNA clone, designated l ID, has b~.~n isolated from human melanoma cells and encodes a MSH receptor. The cloned eDNA encodes a 317 amino acid protein with transmembrane topography characteristics of a G-protein.coupled receptor, bat it does not show striking similarity to already pablish~ sequences of other G-protein-coupl~ receptors. When 11D eDNA is expressed in COS-7 cells, it binds an Z~l-labelled MSH analogue (NDP-MSH) in a Sl~Cifie manner. The bound ligand could be displaced by melanotropie peptides, a~-MSH, fl.MSH, 7-MSH and ACTH (adrenoeonieotropie hormone), but not by the non-melanotropie ~ptid¢,/3-endorphine. This is the first report of the cloning of a receptor geae of the melanotropin receptor family.

Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

“…In this light, the difference in the side chain conformations of the Trp residue of MT-II (gauche-(−), χ 1 = −78°) and PG-951 (trans, χ 1 = −177°) may be responsible for the hMC3R selectivity observed for PG-951. Compound 10 (PG-952), with D-Phe 4 and D-Nal(2′) 7 residues, was found to be a weak partial agonist at the hMC3R (EC 50 = 55 nM), and an antagonist at hMC4 and hMC5 receptors with a low selectivity (hMC4/hMC5 = 14). Finally, since previously, we demonstrated that inserting a D-Nal(2′) residue in 9 position makes it possible to modulate the activity on hMC5R [25], we synthesized two analogues in which we replaced the position 4 with a D-Phe and in position 9, the Trp with a D-Nal(2′).…”

“…There are five known melanocortin receptor (MCR) subtypes, all of which belong to the family of seven transmembrane G-protein coupled receptors (GPCRs), and whose activation is linked to the generation of intracellular cAMP [3,7,8,12,[14][15][16]22,31,34,38]. Importantly, the interaction of the melanocortin peptides with their receptors can be modified by two endogenous protein antagonists, agouti, and agouti-related protein, which are the products of two distinct genes [33,35].…”

Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

“…The Y152X variant and the previously described variants, R151C and R142H, occur in the second intracellular region of the protein, which has been found to contain two sequences for cAMP-dependent protein kinase recognition: from amino acid 142 to 145 and from 151 to 156. Additionally, one other such region is located in the COOH-terminal region (amino acids 306 to 308) (Chhajlani and Wikberg, 1992). The three variants therefore may lead to the production of a protein without sufficient function for signalling cAMP.…”

Melanocortin receptors mediate α-MSH-induced stimulation of neurite outgrowth in neuro 2A cells

“…To date, five melanocortin receptor (MC-R) subtypes have been identified [3,[7][8][9][12][13][14][15][24][25][26]30]. Three of these, MC3-R, MC4-R and MC~-R are expressed in the nervous system.…”