CONICET | Buscador de Institutos y Recursos Humanos

Abstract?The melanocortin 4 receptor (MC4R) is a Gprotein-coupled receptor (GPCR) that is expressed in severalbrain nuclei playing a crucial role in the regulation ofenergy balance controlling the homeostasis of the organism.It displays both agonist-evoked and constitutive activity,and moreover, it can couple to different G proteins.Most of the research on MC4R has been focused onagonist-induced activity, while the molecular and cellularbasis of MC4R constitutive activity remains scarcely studied.We have previously shown that neuronal N-typevoltage-gated calcium channels (CaV2.2) are inhibited byMC4R agonist-dependent activation, while the CaV subtypesthat carry L- and P/Q-type current are not. Here, we testedthe hypothesis that MC4R constitutive activity can affectCaV, with focus on the channel subtypes that can controltranscriptional activity coupled to depolarization (L-type,CaV1.2/1.3) and neurotransmitter release (N- and P/Q-type,CaV2.2 and CaV2.1). We found that MC4R constitutive activityinhibits specifically CaV1.2/1.3 and CaV2.1 subtypes ofCaV. We also explored the signaling pathways mediatingthis inhibition, and thus propose that agonist-dependentand basal MC4R activation modes signal differentiallythrough Gs and Gi/o pathways to impact on different CaVsubtypes. In addition, we found that chronic incubation withMC4R endogenous inverse agonist, agouti and agoutirelatedpeptide (AgRP), occludes CaV inhibition in a cell lineand in amygdaloid complex cultured neurons as well. Thus,we define new mechanisms of control of the main mediatorsof depolarization-induced calcium entry into neurons bya GPCR that displays constitutive activity. 2017 IBRO.Published by Elsevier Ltd. All rights reserved.