Ghrelin receptor (GHSR) and dopamine receptor type 2 (D2R) co-expression modifies each receptor´s effects on voltage gated calcium channel CaV2.2

CORDISCO GONZALEZ, SANTIAGO; MUSTAFÁ, EMILIO ROMÁN; RODRÍGUEZ, SILVIA SUSANA; RAINGO, JESICA

Cordoba

Congreso; XXXIII Congress of the Argentine Society for Research in Neuroscience; 2018

Sociedad Argentina de investigación en Neurociencias

Presynaptic CaV2.2 are activated by action potentials, and their calcium current induces neurotransmitter release. In this context, regulating CaV2.2 is critical, and one of the most important mechanisms for doing so is through G-protein coupled receptor (GPCR) activity. Two such GPCRs are the ghrelin receptor (GHSR) and the dopamine receptor type 2 (D2R). We have previously demonstrated that GHSR constitutive activity reduces CaV2.2 trafficking to the plasma membrane and that ghrelin-induced GHSR activity inhibits CaV2.2 currents. On the other hand, dopamine-mediated activation of D2R also inhibits CaV2.2 currents. It has been recently shown that D2R and GHSR hetero-dimerize in hypothalamic neurons. Here we explore how co-expression of GHSR and D2R modulates the effect that each GPCR has individually on CaV2.2. We found that GHSR-D2R co-expression increases the basal inhibition of CaV2.2 by GHSR constitutive activity, since less GHSR is needed to reduce CaV2.2 currents when D2R is co-transfected. By contrast, the acute inhibitory effect of ghrelin on CaV2.2 currents is unaffected by GHSR-D2R co-expression. Meanwhile, GHSR-D2R co-expression decreases inhibition of CaV2.2 by dopamine-evoked D2R activity (increase in EC50), since a higher dopamine concentration is needed to inhibit CaV2.2 currents when GHSR is co-transfected. This last effect depends on GHSR constitutive activity, since it is occluded by pre-incubation with Substance-P analog 1 µM, a GHSR inverse agonist.