Ghrelin receptor signaling in the hypothalamus. (A) Hypothalamic circuits involved in ghrelin-mediated feeding behavior. Two distinct neuronal populations in the ARC represented by ArGP/NPY/GABA neurons and POMC/CART neurons are considered first-order sensory neurons in the control of food intake. They project to anorexigenic neurons in the PVN and orexigenic neurons in the PFA and LHA, which in turn project to the NTS to control feeding behavior. Upon stimulation of ArGP/NPY/GABA neuron activity by ghrelin, POMC/CART neurons are inhibited through GABAergic input from activated ArGP/NPY/GABA neurons, which in turn suppress the anorexigenic tone in the PVN. This inhibition may be balanced by the inhibition of Ca_v2.1 and Ca_v2.2 channels on the ArGP/NPY/GABA neurons by presynaptic GHSR1a (dotted circle). This in turn inhibits GABA release and suppresses inhibitory GABAergic input of POMC/CART neurons. The orexigenic and anorexigenic pathways are outlined in green (plus symbols) and red (minus symbols), respectively. (B) GHSR1a-mediated inhibition of presynaptic Ca_v2.1 and Ca_v2.2 channels occurs via two distinct mechanisms: (1) an agonist-dependent inhibition that involves the activation of Gαq-coupled receptors and a direct channel inhibition by Gβγ dimer; and (2) an agonist-independent inhibition mediated by constitutive GHSR1a activity and Gαi/o signaling that not only supports Gβγ-mediated inhibition but also decreases channel density in the plasma membrane, possibly by stimulating the internalization of channel–receptor complexes or by suppressing channel trafficking to the cell surface.