Appetite is suppressed by the peptide α-melanocyte–stimulating hormone (α-MSH) and stimulated by the Agouti-related peptide (AgRP). Binding of α-MSH to the G protein–coupled receptor (GPCR) MC4R stimulates the G protein Gαs, leading to activation of protein kinase A (PKA); AgRP competes with α-MSH for binding to MC4R and blocks the constitutive activity of MC4R. Ghamari-Langroudi et al. found that the MC4R-dependent effects of α-MSH and AgRP on appetite were mediated by a G protein–independent mechanism in the paraventricular nucleus (PVN), a region of the hypothalamus that controls appetite. Application of α-MSH to slices from mouse hypothalamus stimulated depolarization of MC4R-positive PVN neurons, and AgRP caused hyperpolarization of these cells. Various inhibitors of Gαs-PKA signaling had no effect on the firing of these neurons in response to α-MSH. Characterization of the currents in these neurons suggested that α-MSH triggered depolarization by reducing inward-rectifying K+ currents and that AgRP triggered hyperpolarization by increasing inward-rectifying K+ currents. Pharmacological and electrophysiological experiments in neurons and in HEK293 cells indicated that the inward-rectifying K+ (Kir) channel Kir7.1 mediated these responses. AgRP induced opening of Kir7.1, and α-MSH induced closure of Kir7.1 in a MC4R-dependent manner, but neither event required G proteins or PKA. An AgRP analog that promotes MC4R-dependent G protein signaling, yet has reduced ability to stimulate appetite in rats, did not induce opening of Kir7.1 in cultured cells. The authors identified an α-MSH analog that stimulated closing of Kir7.1, depolarized cultured PVN neurons, and suppressed appetite in mice, but did not elicit G protein–dependent MC4R responses in vivo. This α-MSH analog also reduced growth of zebrafish in a Kir7.1-dependent manner. Thus, MC4R signals independently of G proteins to control appetite, although the precise mechanism by which MC4R controls Kir7.1 activity remains to be determined.
M. Ghamari-Langroudi, G. J. Digby, J. A. Sebag, G. L. Millhauser, R. Palomino, R. Matthews, T. Gillyard, B. L. Panaro, I. R. Tough, H. M. Cox, J. S. Denton, R. D. Cone, G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 520, 94–98 (2015). [PubMed]