Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons

• Autores: López Soto, Eduardo Javier; Agosti, Francina; Cabral, Agustina; Mustafa, Emilio Román; Martínez Damonte, Valentina; Gandini, María Alejandra; Rodriguez, Silvia Susana; Castrogiovanni, Daniel; Felix, Ricardo; Perelló, Mario; Raingo, Jesica
• Año de publicación: 2015
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Biología Celular, Microbiología; ciencias biológicas; Hormonas; Neurotransmisores
• Institución: Comisión de Investigaciones Científicas de la Provincia de Buenos Aires

The growth hormone secretagogue receptor type 1a (GHSR1a) has the highest constitutive activity of any G protein coupled receptor (GPCR). GHSR1a mediates the action of the hormone ghrelin and, its activation increases transcriptional and electrical activity in hypothalamic neurons. It is known that GHSR1a is present at some specific GABAergic presynaptic terminals; however, its impact on neurotransmitter release remains elusive. The voltage gated calcium channels, CaV2.1 and CaV2.2, control neurotransmitter release at presynaptic terminals and their activities are modulated by many GPCRs. Here we show that constitutive as well as agonist-dependent GHSR1a activation trigger a strong impairment of both CaV2.1 and CaV2.2 currents in rat and mouse neurons and in a heterologous expression system. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/o-dependent mechanism that involves persistent reduction in channel density at plasma membrane, whereas, ghrelin-dependent GHSR1a inhibition is reversible and involves altered CaV2 current gating via a Gq-dependent pathway. Thus, we show that GHSR1a differentially inhibits CaV2 channels by Gi/o- or Gq-protein pathways depending on its activation mode. Moreover, we present evidence suggesting that GHSR1a-mediated inhibition of CaV2 impairs GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation by the disinhibition of postsynaptic neurons.