G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

Abstract

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 signaling, including the gene dosage effect of MC4R4, and the sustained effects of AgRP on food intake5.

Cognitive and autonomic determinants of energy homeostasis in obesity

“…106,107 AgRP has been described as an endo genous inverse agonist of MC4R, and as a biased agonist that can produce MC4R-medited effects, an action that is independent of its inhibition of α-MSH binding. 108,109 AgRP, as an anabolic peptide, opposes MC4R-mediated catabolic action. 75,110 Similar to synthetic melanocortin receptor antagonists, AgRP leads to increased food intake and limits energy expenditure.…”

Cardiovascular Regulation by the Arcuate Nucleus of the Hypothalamus

“…This is due to the ability of AgRP neurons to directly influence the activity of POMC neurons (27). In addition, ARC AgRP and POMC neurons are able to modulate the activity of second-order neurons beyond the release of AgRP (28) and α-MSH (29), respectively. This divergent capacity of ARC neurons is due to the fact that often they contain more than one biologically active molecule.…”

Single-molecule insights into mRNA dynamics in neurons

“…To complement these and other unbiased techniques, single molecule detection of endogenous mRNAs has enabled researchers to probe the precise quantity and the exact location of each transcript within single neurons in culture (Figure 1). Further, single molecule labeling of endogenous RNA in brain tissue is beginning to put in vitro measurements into their biological context [14,16,25–29] and can even quantify the co-expression of distinct mRNA species in a single neuron in vivo [28]. The presence of such a diverse population of mRNA in neurites underscores the significance of compartmentalized gene expression in neurons and indicates that a large repertoire of proteins may be necessary to achieve neuronal function within specific compartments.…”