Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances.

The hypothalamic melanocortin system is crucial for the control of appetite and body weight. Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of energy homeostasis, with the MC4R having the major influence. It is generally thought that the main impact of the melanocortin system on hypothalamic circuits is external to the arcuate nucleus, and that any effect locally in the arcuate nucleus is inhibitory on proopiomelanocortin-expressing (POMC) neurons. In contrast, using current- and voltage-clamp recordings from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons and a separate arcuate neuronal population identified by the rat insulin 2 promoter (RIPCre) transgene expression. Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP), hyperpolarizes POMC and RIPCre neurons in the absence of melanocortin agonist, consistent with inverse agonism at the MC4R. A decreased transient outward (I(A)) potassium conductance, and to a lesser extent the inward rectifier (K(IR)) conductance, underlies neuronal depolarization, whereas an increase in I(A) mediates AgRP-induced hyperpolarization. Accordingly, POMC and RIPCre neurons may be targets for peptide transmitters that are possibly released locally from AgRP-expressing and POMC neurons in the arcuate nucleus, adding further previously unappreciated complexity to the arcuate system.