Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut

胃肠(GI)运动受肠道起搏细胞、平滑肌细胞和肠道的控制。 神经系统(ENS)作为肠道中的“第二大脑”独立运作。ENS异常导致许多 胃肠动力障碍。1899年，贝利斯和斯塔林提出了经典的“肠道定律”，指出 “在肠道的任何一点兴奋，在上面刺激收缩，在下面抑制”，这表明明显的内在的 机械力可以引起兴奋性和抑制性肠道运动行为。最近的研究表明 还证明了机械敏感性是驱动肠道运动行为所必需的，例如结肠 由ENS直接激活或由5-羟色胺释放引起的移行性运动复合体(CMMC) 肠嗜铬细胞(ECs)通过机械力作用于肠道上皮细胞。然而，分子、细胞和 控制肠道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转导中起着至关重要的作用。最近令人兴奋的研究已经 确定机械敏感的Piezo通道是皮肤中机械力的分子传感器 极大地提高了我们对Piezo通道在我们的光触觉中的作用的了解 和机械性疼痛。然而，Piezo通道在肠道和心脏的机械敏感性中所起的作用 人们对其他内脏器官知之甚少。初步研究表明，Piezo1的化学激活 促进结肠收缩并增加CMMC频率，表明Piezo1在功能上得到了表达 胆碱能兴奋性神经回路和氮能肠神经回路。更重要的是，Piezo1需要 活体内结肠运动正常。因此，我们假设Piezo1是一种机械力的分子传感器 胃肠道，可能成为治疗胃肠道动力障碍的药物靶点，如 慢传输型便秘。 为了验证这一假设，我们将采用多学科方法，使用活细胞钙成像，膜片钳 结合小鼠遗传学和肠道运动行为的记录和药理学方法 方法阐明Piezo1介导的细胞和分子机制 ENS和肠上皮均存在机械敏感性。这些研究的成功完成将会推动 我们对之前未知的Piezo1和Piezo1表达的肠神经元和 ECS在胃肠动力控制中的作用。更重要的是，这些研究将为发展提供新的机遇 治疗胃肠道动力障碍的有效和更安全的药物。

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.