Two signaling pathways mediate presynaptic voltage gated calcium channels inhibition by ghrelin receptor activation

LOPEZ SOTO EJ; AGOSTI F; MARTINEZ DAMONTE V; MUSTAFA ER; RODRIGUEZ S; RAINGO J

Huerta Grande, Córdoba

Congreso; XXIX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2014

Sociedad Argentina de Investigación en Neurociencia

Growth hormone secretagogue receptor type 1a (GHSR1a) has the highest constitutive activity of any G protein coupled receptor (GPCR). GHSR1a mediates the orexigenic effects of the gut-derived hormone ghrelin, which plays an important role in the control of food intake and other homeostatic functions. GHSR1a is present at presynaptic terminals in the hypothalamus and it regulates neuronal activity, but the mechanism of its actions remains poorly understood. Presynaptic voltage gated calcium channels, CaV2.1 and CaV2.2, control neurotransmitter release and their activities are modulated by GPCRs. Here we show that constitutive as well as agonist-dependent GHSR1a activation triggers a strong impairment of both CaV2.1 and CaV2.2 currents. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/odependent mechanism that involves persistent reduction in channel numbers in the plasma membrane, whereas, ghrelin-dependent GHSR1a inhibition is reversible and involves altered CaV2 current gating via a Gq-dependent pathway. Additionally, this inhibitory pathway requires Gβɣ dimers and elicits different profiles depending on the β-subunit subtype. Interestingly, we found that inhibition of both CaV2.1 and CaV2.2 activity by GHSR1a activation impacts consequently inhibiting GABAergic transmission in hypothalamic neurons. Thus our data show that GHSR1a activity is key factor mediating overall CaV2 channel function and modulate GABAergic neurotransmission in hypothalamic neurons.