AGONIST-INDUCED MELANOCORTIN TYPE 4 RECEPTOR (MC4R) ACTIVITY SPECIFICALLY INHIBITS NEURONAL CAV2.2 CHANNELS

AGOSTI F; LOPEZ SOTO JE; CABRAL A; CASTROGIOVANNI D; RODRÍGUEZ SS; SCHIOTH HB; PERELLO M; RAINGO J

Huerta Grande

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2013

Sociedad Argentina de Neurociencia

MC4 is a G protein coupled receptor highly expressed in neurons involved inappetite control. MC4 mutations are, by far, the most common cause of monogenic obesity in humans. MC4 activity impacts in many aspects of neuron function, including synaptic activity. Moreover, MC4 exhibits basal activity. Presynaptic neuronal VOCCs control neurosecretion. Two different genes encode presynaptic VOCCs CaV2.1 and CaV2.2. These channels are highly sensitive to G protein coupled receptors mediated modulation. Here, we investigated how MC4 basal and evoked activity impact on CaV2.1 and CaV2.2 function. We used the patch clamp technique in transfected HEK293 cells coexpressing CaV2.1 or CaV2.2, the auxiliary subunits of calcium channels and the MC4. We found that MC4 co-expression reduced CaV2.1 basal calcium currents while it did not alter CaV2.2 basal current levels. When we applied the MC agonist MTII to HEK293 cells co-expressing CaV2.2 and MC4, we found a concentration dependent inhibitory effect on CaV2.2 currents. When we evaluated MTII effect on 5 cells co-expressing CaV2.1 and MC4 that displayed calcium currents we found no effect of MTII. Our results suggest that MC4 activity would have a differential effect on the two major presynaptic calcium channels: CaV2.1 is inhibited by basal MC4 activity and CaV2.2 is sensitive to agonist-evoked MC4 activity. We are now investigating these two separated pathways in terms of the G protein and second messengers involved.