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Voltage-gated calcium channels type 2.2 (Ca V 2.2) are activated by action potentials at presynaptic terminals, and their calcium current induces neurotransmitter release. In this context, regulating Ca V 2.2 is critical, and one of the most important mechanisms for doing so is through its G protein-coupled receptor (GPCR) activity. Two such GPCRs are the ghrelin (GHSR) and the dopamine type 2 (D2R) receptors. We previously demonstrated that constitutive GHSR activity reduces Ca V 2.2 forward trafficking and that ghrelin-induced GHSR activity inhibits Ca V 2.2 currents. On the other hand, dopamine-induced D2R activity also inhibits Ca V 2.2 currents. It has been recently shown that D2R and GHSR form heteromers in hypothalamic neurons. This interaction profoundly changes the signaling cascades activated by dopamine and is necessary for dopamine-dependent anorexia. Here we explored how D2R-GHSR coexpression in HEK293T cells modulates the effect that each GPCR has on Ca V 2.2. We found that D2R-GHSR coexpression reduces the inhibition of Ca V 2.2 currents by agonist-induced D2R activation and added a new source of basal Ca V 2.2 current inhibition to the one produced by GHSR solely expression. We investigated the signaling cascades implicated and found that constitutive GHSR activity, G q protein, and Gβγ subunit play a critical role in these altered effects. Moreover, we found that the effect of D2R agonist on native calcium currents in hypothalamic neurons is reduced when both D2R and GHSR are overexpressed. In summary, our results allow us to propose a novel mechanism for controlling Ca V 2.2 currents involving the coexpression of two physiologically relevant GPCRs.

Dopamine Receptor Type 2 and Ghrelin Receptor Coexpression Alters CaV2.2 Modulation by G Protein Signaling Cascades

Dopamine Receptor Type 2 and Ghrelin Receptor Coexpression Alters Ca_V2.2 Modulation by G Protein Signaling Cascades