Melanocortin 4 receptor (MC4R) constitutive activity impairs L-type voltage- gated calcium channels

AGOSTI F; E JAVIER LOPEZ SOTO; RODRÍGUEZ SS; RAINGO J

Montpellier

Congreso; 12th meeting of the French Neuroscience Society; 2015

French Neuroscience Society

Melanocortin 4 receptor (MC4R) mutations are, by far, the most common cause of monogenic obesity in humans. MC4R is highly expressed in specific sites of the brain, such as the paraventricular nucleus of the hypothalamus and the amygdala, where it increases expression of appetite-related genes by mechanisms that are not completely understood. MC4R is a G protein coupled receptor that displays constitutive activity in absence of its natural agonist, αMSH, and this basal activity can be reduced by its natural inverse agonist, AGRP, binding. One plausible mechanism of MC4R activity to increase gene expression is controlling calcium influx through L-type calcium channels (CaV1.2 and CaV1.3), a well-known mechanism that initiates gene expression in neurons. CaV1.2 and CaV1.3 are activated by depolarization and have a wide distribution in the brain. Here, we tested if MC4R regulates CaV1.2 and CaV1.3 activity using the patch clamp technique in HEK293t cells co-expressing CaV1.2 or CaV1.3, the auxiliary calcium channel subunits and MC4R. We found that MC4R co-expression did not modify CaV1.2 and CaV1.3 biophysical properties, such as voltage activation and kinetics. However, we observed an inverse correlation between the amount of transfected MC4R cDNA and CaV1.2 and CaV1.3 current levels, suggesting an effect of MC4R constitutive activity on L-type calcium channels function. We found that AgRP restored the CaV1.2 and CaV1.3 basal currents while cholera toxin, a Gs pathway blocker, failed to block MC4R constitutive activity. The last result wasn?t expected since the bibliography describes MC4R constitutive activity as a Gs signaling pathway, so now we are studying how this mechanisms can inhibit L-type calcium channels. So far, we know that MC4R constitutive activity inhibits L-type calcium channels by a Gs independent mechanism and this could be a possible mechanism to modulate gene expression activation by MC4R in neurons.