title: Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells.
abstract: Mouse melanocortin receptors, MC1-R, MC3-R, MC4-R, and MC5-R, when expressed in HEK293 cells and stimulated with either alpha-melanocyte-stimulating hormone (alpha-MSH) or desacetyl-alpha-MSH, mediate increases in intracellular free calcium concentration ([Ca(2+)](i)) with EC(50) values between 0.3 and 4.3 nM. The increase in [Ca(2+)](i) is cholera toxin sensitive and pertussis toxin insensitive. The mechanism involves calcium mobilization from intracellular stores without a transient rise in inositol trisphosphate. Mouse agouti protein (55 nM) is a competitive antagonist of alpha-MSH (6-fold) and desacetyl-alpha-MSH (8-fold), coupling the mMC1-R to increased [Ca(2+)](i). Agouti protein (55 nM) significantly increased the EC(50) for alpha-MSH (3-fold), and 550 nM agouti protein significantly increased the EC(50) for desacetyl-alpha-MSH (4-fold), coupling the mMC4-R to a rise in [Ca(2+)](i). However, agouti protein antagonism of the MC4-R may not be competitive since there was a trend for the maximum response to also increase. There was no significant antagonism of the MC3-R and MC5-R by agouti protein (55 nM). Understanding the physiological relevance of the transduction of a calcium signal by melanocortin peptides may be important for future development of therapeutic targeting of the melanocortin receptors.
authors.affiliation: Research Centre for Developmental Medicine and Biology, Department of Paediatrics, School of Biological Sciences, University of Auckland, Auckland 1, New Zealand. kmountjoy@auckland.ac.nz
authors.forename: K G
authors.initials: KG
authors.lastname: Mountjoy
authors.forename: P L
authors.initials: PL
authors.lastname: Kong
authors.forename: J A
authors.initials: JA
authors.lastname: Taylor
authors.forename: D H
authors.initials: DH
authors.lastname: Willard
authors.forename: W O
authors.initials: WO
authors.lastname: Wilkison
mesh_terms: D054366:Agouti Signaling Protein; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D015759:Ionomycin / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000502:physiology*; D044101:Receptors, Melanocortin; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C515182:ASIP protein, human; D054366:Agouti Signaling Protein; D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D036341:Intercellular Signaling Peptides and Proteins; C470053:Mc3r protein, mouse; D010446:Peptide Fragments; D011506:Proteins; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C515183:a protein, mouse; D008345:Manganese; D015759:Ionomycin; D000521:alpha-MSH; D019284:Thapsigargin; D002217:Carbachol; D002772:Cholera Toxin; D002118:Calcium