Mechanically activated Piezo2 channels are key players in somatosensory touch, but their regulation by cellular signaling pathways is poorly understood. Dorsal root ganglion (DRG) neurons express a variety of G-protein-coupled receptors that modulate the function of sensory ion channels. Gi-coupled receptors are generally considered inhibitory, as they usually decrease excitability. Paradoxically, activation of Gi-coupled receptors in DRG neurons sometimes induces mechanical hypersensitivity, the mechanism of which is not well understood. Here, we find that activation of Gi-coupled receptors potentiates mechanically activated currents in DRG neurons and heterologously expressed Piezo2 channels, but inhibits Piezo1 currents in heterologous systems in a Gβγ-dependent manner. Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) also abolishes the potentiation of Piezo2 currents. Local injection of sumatriptan, an agonist of the Gi-coupled serotonin 1B/1D receptors, increases mechanical sensitivity in mice, and the effect is abolished by inhibiting PI3K and MAPK. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents and alter mechanosensitivity after activation of Gi-coupled receptors.

中文翻译：

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Gi 偶联受体激活通过 Gβγ 增强 Piezo2 电流。

机械激活的 Piezo2 通道是体感触觉的关键参与者，但人们对它们通过细胞信号通路的调节知之甚少。背根神经节 (DRG) 神经元表达各种调节感觉离子通道功能的 G 蛋白偶联受体。Gi 偶联受体通常被认为是抑制性的，因为它们通常会降低兴奋性。矛盾的是，DRG 神经元中 Gi 偶联受体的激活有时会引起机械超敏反应，其机制尚不清楚。在这里，我们发现 Gi 偶联受体的激活增强了 DRG 神经元中的机械激活电流和异源表达的 Piezo2 通道，但以 Gβγ 依赖性方式抑制异源系统中的 Piezo1 电流。Gβγ下游激酶的药理学抑制，磷酸肌醇 3-激酶 (PI3K) 和丝裂原活化蛋白激酶 (MAPK) 也消除了 Piezo2 电流的增强作用。局部注射舒马曲坦（一种 Gi 偶联血清素 1B/1D 受体的激动剂）可增加小鼠的机械敏感性，并通过抑制 PI3K 和 MAPK 消除这种作用。因此，我们的研究说明了 Gβγ 在激活 Gi 偶联受体后对 Piezo2 电流敏感和改变机械敏感性的间接作用机制。