Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut

胃肠道（GI）运动由肠起搏细胞、平滑肌细胞和肠上皮细胞控制。 神经系统（ENS）作为肠道中的“第二大脑”独立发挥作用。ENS异常导致许多 胃肠道动力障碍。1899年，Bayliss和Starling提出了经典的“肠道定律”，指出 “肠道任何一点的兴奋都会引起上面的收缩，下面的抑制”，这表明不同的内在 机械力可以引起兴奋性和抑制性肠运动行为。最近的研究 还证明了机械敏感性是驱动肠道运动行为所必需的， 移行性运动复合体（CMMC），由ENS的直接激活或由 肠嗜铬细胞（EC）在肠道上皮细胞的机械力。然而，这些分子、细胞和 控制肠道中机械敏感性过程的神经回路仍然知之甚少。 膜结合离子通道在机械力传递中起着重要作用。最近令人兴奋的研究 将机械敏感压电通道确定为皮肤中机械力的分子传感器， 大大提高了我们对压电通道在我们的轻触感觉中的作用的认识 和机械性疼痛然而，压电通道在肠道机械敏感性中的作用， 对其他内脏器官了解甚少。初步研究表明，Piezo1的化学活化 促进结肠收缩并增加CMMC频率，表明Piezo1在功能上表达 通过胆碱能兴奋性和氮能肠神经回路。更重要的是，需要Piezo1 体内正常结肠运动。因此，我们假设Piezo1是一个分子传感器的机械力， 胃肠道，并可能作为治疗药物的目标，用于治疗胃肠道动力障碍， 慢传输型便秘 为了验证这一假设，我们将采取多学科的方法，使用活细胞Ca2+成像，膜片钳 记录和药理学方法结合小鼠遗传学和肠道运动行为 方法来阐明Piezo 1介导的细胞和分子机制 ENS和肠上皮的机械敏感性。成功完成这些研究将促进 我们对Piezo1和表达Piezo1的肠神经元先前未被认识的作用的理解， EC控制GI运动。更重要的是，这些研究将为发展 有效和更安全的胃肠动力障碍药物。

Gastrointestinal (GI) motility is controlled by intestinal pacemaker cells, smooth muscle cells and the enteric nervous system (ENS) acting independently as the “second brain” in the gut. ENS abnormalities cause many GI motility disorders. In 1899, Bayliss and Starling proposed the classic “The law of the intestine” stating that “excitation at any point of the gut excites contraction above, inhibition below”, suggesting that distinct intrinsic excitatory and inhibitory intestinal motor behaviors can be elicited by mechanical forces. Recent studies have also demonstrated that mechanosensitivity is required to drive intestinal motor behaviors such as the colonic migrating motor complex (CMMC) resulting from either direct activation of ENS or by serotonin release from enterochromaffin cells (ECs) in the gut epithelium by mechanical forces. However, the molecules, cells, and neural circuits governing the process of mechanosensitivity in the gut still remain poorly understood. Membrane-bound ion channels play an essential role in mechanotransduction. Recent exciting studies have identified the mechanosensitive Piezo channels as molecular sensors for mechanical forces in the skin and have significantly advanced our knowledge about the role of the Piezo channels in our senses of light touch and mechanical pain. However, The role of Piezo channels involved in the mechanosensitivity in the gut and other visceral organs is poorly understood. Preliminary studies showed that chemical activation of Piezo1 promotes colon contraction and increases CMMC frequency, suggesting that Piezo1 is functionally expressed by both cholinergic excitatory and nitrergic enteric neural circuits. More importantly, Piezo1 is required for normal colonic motility in vivo. We thus hypothesize that Piezo1 is a molecular sensor for mechanical forces in the GI tract and potentially could serve as a therapeutic drug target for treating GI motility disorders such as slow transit constipation. To test this hypothesis, we will take a multidisciplinary approach using live-cell Ca2+ imaging, patch-clamp recordings and pharmacological approaches in combination to mouse genetics and intestinal motor behavioral methods to elucidate the cellular and molecular mechanisms underlying the Piezo1-mediated mechanosensitivity in both ENS and intestinal epithelium. Successful completion of these studies will advance our understanding of the previously unrecognized roles of Piezo1 and Piezo1-expressing enteric neurons and ECs in controlling GI motility. More importantly, these studies will offer new opportunities for developing effective and safer medicines for GI motility disorders.