Agonist-induced melanocortin type 4 receptor (MC4R) activity specifically inhibits neuronal CaV2.2 channels

FRANCINA AGOSTI; EDUARDO JAVIER LOPEZ SOTO; AGUSTINA CABRAL; DANIEL CASTROGIOVANNI; SILVIA RODRIGUEZ; HELGI B.SCHIOTH; MARIO PERELLÓ; JESICA RAINGO

Congreso; Sociedad Argentina de Neurociencias. XXVIII Annual Meeting.; 2013

MC4R is a G-protein coupled receptor involved in food intake and energyexpenditure. MC4R is expressed at brain nuclei that operate as centers of bodyweight regulation, such as PVN of the hypothalamus, amygdala and NTS. MC4Ractivation modifies neuronal activity but the molecular mechanisms by which thisprocess occurs remain unclear. Here we studied how MC4R evoked activation canregulate voltage-gated calcium channels (VGCC). Using patch clamp we found thatMC4R activation by MTII, a MC3/4R agonist, inhibited CaV2.2 current in transientlytransfected HEK293 cells. This inhibition was concentration-dependent, voltageindependentand occluded by cholera toxin (Gαs inhibitor). Moreover, we foundthat MTII specifically inhibited native CaV2.2 currents from mouse culturedamygdalar neurons in a concentration-dependent manner. Then we compared theeffect of mouse icv injections of the MC4R specific agonist (RO27-3225) and CaV2.2blocker (ω conotoxinGVIA). RO27-3225 activated mice neurons in severalamygdalar subregions while ω conotoxin GVIA mimicked the increase of c-Fosexpression induced by RO27-3225 exclusively in the Central Amygdala nucleus(CeA). Our data shows that a presynaptic VGCC subtype, the CaV2.2, is specificallyinhibited by MC4R activation. From our in vitro and in vivo studies on amygdalarneurons, and since CeA has abundant GABAergic innervations, we postulate thatinhibition of CaV2.2 by MC4R could reduce the GABA release decreasing theinhibitory tone on CeA