G-protein independent coupling of the MC4R to Kir 7.1 in hypothalamic neurons

The regulated release of anorexigenic α-MSH and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the CNS plays a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data showα-MSH is an agonist that couples the receptor to the Gαs signaling pathway1, while AgRP binds competitively to block α-MSH binding2, and block the constitutive activity mediated by the ligand-mimetic amino terminal domain of the receptor3. Here, we show that regulation of firing activity of hypothalamic PVN neurons by α-MSH and AgRP can be mediated independently of Gαs signaling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Further, 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 signaling appears 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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Author InformationCorrespondence may be addressed to either M.G-L. ([email protected]) or R.D.C. ([email protected]). The authors declare no competing financial interests Supplementary Information is available in the online version of the paper. Author Contributions M.G-L., G.J.D, J.A.S., R.M., H.M.C., J.D., & R.D.C designed experiments, M.G-L., G.J.D., J.A.S, R.M., B.L.P., T.G., and I.R.T., performed experiments, G.L.M. and R.P. synthesized, purified, and folded the AgRP mini peptide, and M.GL. and R.D.C. analyzed the data and wrote the manuscript. All authors reviewed and commented on the manuscript. HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2015 October 02. Published in final edited form as: Nature. 2015 April 2; 520(7545): 94–98. doi:10.1038/nature14051. A uhor M anscript