Melanocortin 4 receptor (MC4R) constitutive activity impairs specific voltage-gated calcium channels subtypes.

CORDISCO G. SANTIAGO; RODRIGUEZ SILVIA S.; PERELLÓ MARIO; RAINGO JESICA ; AGOSTI F

Congreso; XXX reunion anual de la Sociedad Argentina de investigaciones en neurociencias; 2015

Sociedad Argentina de investigaciones en neurociencias

MC4R regulates food intake and energy expenditure. MC4R is a G protein coupled receptor mostly expressed in the paraventricular nucleus of the hypothalamus and the amygdala. Despite MC4R activity level increases by agonist binding, MC4R displays constitutive activity that is abolished by its endogenous inverse agonist, AgRP. MC4R mutations that modify constitutive activity cause unbalanced food intake and obesity in humans. We recently demonstrated that MC4R activation by agonist can reduce presynaptic CaV2.2 currents, but the neuronal mechanisms activated by constitutive activity are unknown. Hence, we tested if MC4R regulates CaV subtypes activity using the patch clamp technique in HEK293t cells co-expressing each CaV and MC4R. We observed that cells co-expressing MC4R and CaV1.2, CaV1.3 or CaV2.1 have reduced calcium currents and this effect is occluded by AgRP, while CaV2.2 currents are not affected. By pharmacological manipulations we found that Gi/o but not Gs protein is involved in the pathways utilize by MC4R constitutive activity to reduce CaV currents. Moreover, we found that MC4R constitutive activity signaling requires ERK1/2 protein phosphorylation to impair basal CaV1.3 currents. Thus, we conclude that CaV subtype targeted by MC4R and the intracellular pathway involved are different for the constitutive and agonist-evoked modes of activation of MC4R.