A role for growth hormone secretagogue receptor type 1a, ghrelin and CaV2 channels in hypothalamic neurotransmission

JESICA RAINGO

Vienna

Simposio; Translational approaches in understanding hedonic eating and neuroplasticity. Annual meeting of the European College of Neuropsychopharmacology (ECNP); 2016

European College of Neuropsychopharmacology

Growth hormone secretagogue receptor type 1a (GHSR1a) mediates orexigenic effects of the ghrelin hormone by regulating transcriptional and electrical activity mainly in hypothalamic neurons. Despite its well-known neuronal activation effects, the molecular mechanisms by which it controls synaptic activity remain elusive. We found that constitutive activity of GHSR1a, the highest basal activity of any known GPCR, dramatically decreases CaV2 currents in neurons. CaV2 channels control neurotransmitter release and they are highly targeted by GPCR-activated heterotrimeric G proteins. We studied this mechanism and found that constitutive activity of GHSR1a triggers a tonic CaV2 current inhibition by decreasing the surface channel density in a CaVβ auxiliary subunit dependent manner. Moreover, we observed that GHSR1a chronic effect depends on the receptor expression levels, turning it in a key factor mediating overall CaV2 channel function in neurons. Moreover, we present evidence suggesting that GHSR1a-mediated inhibition of CaV2 correlates with a decrease of GABA release in neurons, a mechanism that could contribute to well-known GHSR1a-mediated neuronal activation effect by the dis-inhibition of postsynaptic neurons. Thus, our data provide the first evidence that agonist independent GHSR1a activity can impact on synaptic activity by a novel CaV channels regulation.