Ghrelin-evoked GHSR activity impairs low voltage activated Ca2+ channel (CaV3) currents in hypothalamic neurons.

RODRIGUEZ SILVIA S.; MUSTAFÁ EMILIO ROMÁN,; RAINGO JESICA; CORDISCO G. SANTIAGO

Cordoba

Congreso; XXXIII Congreso de la Sociedad Argentina de Investigaciones en Neurociencias; 2018

Sociedad Argentina de Investigaciones en Neurociencias

CaV3 play a critical role in shaping burst firing and controlling pacemaker activity in neurons. Despite the importance of these channels, information regarding the mechanisms modulating CaV3 currents is scarce. In this context, we investigated the sensitivity of CaV3 currents to activation of GHSR, a receptor involved in energy balance and memory, among other central functions. We have previously showed that GHSR decreases CaV1 and CaV2 current in neurons, and that this inhibition impacts neurotransmission in areas where GHSR is physiologically relevant: the hypothalamus and the hippocampus. We performed whole cell patch clamp on hypothalamic neuronal primary cultures and found that ghrelin inhibits CaV3 currents. We next assayed this effect on CaV3 subtypes (CaV3.1-3) isolated in transfected HEK293T cells and found that CaV3.3 is the only CaV3 subtype inhibited by ghrelin in a Gq-dependent and Gβγ-independent manner. For CaV3.3, we observed a 30% reduction in the number of channels available for opening, acceleration of the activation and inactivation kinetics, and no changes in voltage dependency parameters nor in the kinetics of deactivation or recovery from inactivation. Ghrelin application increases V1/2 of steady-state inactivation but does not affect steady-state activation, changing the window current size. Finally, we compile these parameters and run simulations on the program NEURON to model the putative impact of GHSR and CaV3.3 on neuron firing activity.