title: Regulation of the Melanocortin-Sensitive Adenylate Cyclase System by N-Acylated Peptide 71-82 of Type 4 Melanocortin Receptor.
abstract: 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.
authors.affiliation: Laboratory of Molecular Endocrinology, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia. alex_shpakov@list.ru.
authors.forename: A O
authors.initials: AO
authors.lastname: Shpakov
authors.affiliation: Laboratory of Molecular Endocrinology, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: K V
authors.initials: KV
authors.lastname: Derkach
authors.affiliation: Laboratory of Molecular Endocrinology, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: E A
authors.initials: EA
authors.lastname: Shpakova
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001923:Brain Chemistry; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D054878:Lipoylation; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D000521:alpha-MSH / Q000494:pharmacology; D019825:gamma-MSH / Q000494:pharmacology
chemical_list: C467221:N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine; D010446:Peptide Fragments; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044005:Tetrahydroisoquinolines; D014230:Triazoles; D019825:gamma-MSH; D006165:Guanylyl Imidodiphosphate; D000521:alpha-MSH; D000262:Adenylyl Cyclases
keywords: adenylate cyclase; brain; cytoplasmic loop 1; melanocortin receptor; peptide