Voltage-gated calcium channels type 2.2 (CaV2.2) are activated by action potentials at presynaptic terminals, 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 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 CaV2.2 forward trafficking and that ghrelin-induced GHSR activity inhibits CaV2.2 currents. On the other hand, dopamine-induced D2R activity also inhibits CaV2.2 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 CaV2.2. We found that D2R-GHSR coexpression reduces the inhibition of CaV2.2 currents by agonist-induced D2R activation and added a new source of basal CaV2.2 current inhibition to the one produced by GHSR solely expression. We investigated the signaling cascades implicated and found that constitutive GHSR activity, Gq 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 CaV2.2 currents involving the coexpression of two physiologically relevant GPCRs.

中文翻译：

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2型多巴胺受体和Ghrelin受体共表达通过G蛋白信号级联改变CaV2.2调节。

电压门控型钙通道2.2（CaV2.2）被突触前末端的动作电位激活，其钙电流诱导神经递质的释放。在这种情况下，调节CaV2.2是至关重要的，而最重要的机制之一就是通过其G蛋白偶联受体（GPCR）活性。两个这样的GPCR是Ghrelin（GHSR）和2型多巴胺（D2R）受体。我们先前证明，本构性GHSR活性降低了CaV2.2的正向运输，而生长素释放肽诱导的GHSR活性抑制了CaV2.2的电流。另一方面，多巴胺诱导的D2R活性也抑制CaV2.2电流。最近显示D2R和GHSR在下丘脑神经元中形成异聚体。这种相互作用深刻地改变了由多巴胺激活的信号级联反应，这对于依赖多巴胺的厌食症是必需的。在这里，我们探讨了HEK293T细胞中D2R-GHSR的共表达如何调节每个GPCR对CaV2.2的影响。我们发现，D2R-GHSR共表达减少了激动剂诱导的D2R激活对CaV2.2电流的抑制作用，并为GHSR单独产生的基础CaV2.2电流抑制作用增加了新的来源。我们调查了牵连的信号传导级联，发现本构性GHSR活性，Gq蛋白和Gβγ亚基在这些改变的影响中起关键作用。此外，我们发现当D2R和GHSR都过表达时，D2R激动剂对下丘脑神经元中天然钙电流的作用会降低。总之，