Regulation of the Melanocortin-Sensitive Adenylate Cyclase System by N-Acylated Peptide 71-82 of Type 4 Melanocortin Receptor

The peptides structurally corresponding in to cytoplasmic loops of G protein-coupled receptors (GPCR) are able to control functional activity of homologous receptors and the corresponding signaling pathways. Modification of these peptides with hydrophobic radicals enhances their biological activity due to penetration of lipophilic derivatives through the membrane and anchoring near their targets, GPCR. We synthesized an N-palmitoylated peptide Palm-Val-[Lys-Asn-Lys-Asn-Leu-His-Ser-Pro-(Nle)-Tyr-Phe-Phe71-82]-amide-Palm-Val-(71-82) structurally corresponding to cytoplasmic loop 1 of melanocortin 4 receptor (M₄R). We found that in micromolar concentrations it very effectively suppresses stimulation of basal adenylate cyclase activity and basal level of GppNHp binding of heterotrimeric G proteins produced by THIQ and α-melanocyte stimulating hormone (α-MSH), agonists of M₄R homologous to the peptide, in synaptosomal membranes of rat brain. The peptide Palm-Val-(71-82) also reduced, albeit to a significantly less extent, stimulation of adenylate cyclase and G-proteins by M₃R agonist of γ-MSH, due to high homology of the peptide primary structure to M₃R cytoplasmic loop 1. The synthesized peptide with activity of M₄R/M₃R antagonist can be used for the development of regulators of M₄R and M₃R and the corresponding biochemical and physiological processes.