Piezo2 ion channels are critical determinants of the sense of light touch in vertebrates. Yet, their regulation is only incompletely understood. We recently identified myotubularin related protein-2 (Mtmr2), a phosphoinositide (PI) phosphatase, in the native Piezo2 interactome of murine dorsal root ganglia (DRG). Here, we demonstrate that Mtmr2 attenuates Piezo2-mediated rapidly adapting mechanically activated (RA-MA) currents. Interestingly, heterologous Piezo1 and other known MA current subtypes in DRG appeared largely unaffected by Mtmr2. Experiments with catalytically inactive Mtmr2, pharmacological blockers of PI(3,5)P2 synthesis, and osmotic stress suggest that Mtmr2-dependent Piezo2 inhibition involves depletion of PI(3,5)P2. Further, we identified a PI(3,5)P2 binding region in Piezo2, but not Piezo1, that confers sensitivity to Mtmr2 as indicated by functional analysis of a domain-swapped Piezo2 mutant. Altogether, our results propose local PI(3,5)P2 modulation via Mtmr2 in the vicinity of Piezo2 as a novel mechanism to dynamically control Piezo2-dependent mechanotransduction in peripheral sensory neurons.

中文翻译：

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肌管蛋白相关蛋白 2 及其磷脂底物 PIP2 控制 Piezo2 介导的外周感觉神经元机械转导

Piezo2 离子通道是脊椎动物轻触感的关键决定因素。然而，人们对它们的监管还不完全了解。我们最近在鼠背根神经节 (DRG) 的天然 Piezo2 相互作用组中发现了肌管蛋白相关蛋白 2 (Mtmr2)，一种磷酸肌醇 (PI) 磷酸酶。在这里，我们证明 Mtmr2 减弱了 Piezo2 介导的快速适应机械激活（RA-MA）电流。有趣的是，DRG 中的异源 Piezo1 和其他已知的 MA 当前亚型似乎基本上不受 Mtmr2 的影响。使用无催化活性的 Mtmr2、PI(3,5)P2 合成的药理阻滞剂和渗透压力的实验表明，Mtmr2 依赖性 Piezo2 抑制涉及 PI(3,5)P2 的消耗。此外，我们在 Piezo2 中发现了一个 PI(3,5)P2 结合区，但在 Piezo1 中没有，如域交换 Piezo2 突变体的功能分析所示，它赋予对 Mtmr2 的敏感性。总之，我们的结果提出了通过 Piezo2 附近的 Mtmr2 进行局部 PI(3,5)P2 调制，作为动态控制外周感觉神经元中 Piezo2 依赖性机械转导的新机制。