Ghrelin-Evoked GHSR Activity Impairs Low Voltage Activated Ca2+ Channel (CaV3) Currents in Hypothalamic Neurons

MUSTAFÁ, EMILIO ROMÁN; CORDISCO GONZALEZ, SANTIAGO; RAINGO, JESICA

ASN Neuro

ASN American Socierty for Neurochemistry

Año: 2019 vol. 11

1759-0914

CaV3 play a critical role in shaping burst firing and controlling pacemaker activity in neurons. Despite the importance of these channels, information regarding the mechanismsmodulating CaV3 currents is scarce. In this context, weinvestigated the sensitivity of CaV3 currents to activationof GHSR, a receptor involved in energy balance andmemory, among other central functions. We have previouslyshowed that GHSR decreases CaV1 and CaV2 current inneurons, and that this inhibition impacts neurotransmissionin areas where GHSR is physiologically relevant: the hypothalamus and the hippocampus. We performed whole cellpatch clamp on hypothalamic neuronal primary cultures andfound that ghrelin inhibits CaV3 currents. We next assayedthis effect on CaV3 subtypes (CaV3.1-3) isolated in transfected HEK293T cells and found that CaV3.3 is the onlyCaV3 subtype inhibited by ghrelin in a Gq-dependent andGbc-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, andno changes in voltage dependency parameters nor in thekinetics of deactivation or recovery from inactivation.Ghrelin application increases V1/2 of steady-state inactivation but does not affect steady-state activation, changing thewindow current size. Finally, we compile these parametersand run simulations on the program NEURON to model theputative impact of GHSR and CaV3.3 on neuronfiring activity