GHSR activation by ghrelin selectively inhibits CaV3.3 subtype of low-voltage-gated calcium channels

MUSTAFÁ ER; CORDISCO GONZALES SANTIAGO; RAINGO J

Valparaiso

Congreso; SGP 73rd annual symposium / SOBLA annual meeting; 2019

Society of General Physiologist and Sociedad de Biofísicos Latinoamericanos

The mechanisms by which ghrelin controls electricalactivity in the hypothalamus are not fully understood. Oneunexplored target of ghrelin is CaV3, responsible for transientcalcium currents (T-currents) that control neuronal firing. Weinvestigated the effect of ghrelin on CaV3 subtypes and howthis modulation impacts on neuronal activity. We performedwhole-cell patch-clamp recordings in primary mousehypothalamic cultures to explore the effect of ghrelin onT-currents. We also recorded calcium currents fromtransiently-transfected tsA201 cells to study the sensitivityof each CaV3 subtype to GHSR (growth hormone secretagoguereceptor) activation. Finally, we ran a computational modelcombining the well-known reduction of potassium current byghrelin with the CaV3 biophysical parameter modificationsinduced by ghrelin to predict the impact on neuronalelectrical behavior. We found that ghrelin inhibits nativeT-currents in hypothalamic neurons. We determined thatCaV3.3 is the only CaV3 subtype sensitive to ghrelin. Themodulation of CaV3.3 by ghrelin comprises a reduction inmaximum conductance, a shift to hyperpolarized voltages ofthe current-voltage (I-V) and steady-state inactivationcurves, and an acceleration of activation and inactivationkinetics. Our model-based prediction indicates that theinhibition of CaV3.3 would attenuate the stimulation of firingoriginating from the inhibition of potassium currents byghrelin. In summary, we discovered a new target of ghrelin inneurons: the CaV3.3. This mechanism would imply a negativefeed-forward regulation of the neuronal activation exertedby ghrelin. Our work expands the knowledge of the wide range of actions of GHSR, a receptor potentially targeted bytherapeutics for several diseases.