title: G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.
abstract: The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Masoud
authors.initials: M
authors.lastname: Ghamari-Langroudi
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Digby
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Julien A
authors.initials: JA
authors.lastname: Sebag
authors.affiliation: Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA.
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.affiliation: Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Palomino
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Matthews
authors.affiliation: 1] Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37208, USA.
authors.forename: Taneisha
authors.initials: T
authors.lastname: Gillyard
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Panaro
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Tough
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Cox
authors.affiliation: 1] Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cone
mesh_terms: D000200:Action Potentials; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008024:Ligands; D008297:Male; D053486:Melanocortins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000521:alpha-MSH / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; C489477:Kir7.1 channel; D008024:Ligands; C574273:MC4R protein, mouse; D053486:Melanocortins; D024661:Potassium Channels, Inwardly Rectifying; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; D019205:GTP-Binding Protein alpha Subunits, Gs