Cellular and ion channel mechanisms underlying the sense of light touch in mammal

描述（由申请人提供）：轻触觉对日常生活至关重要，但在病理条件下，这种重要的感觉可能会改变，导致感觉功能障碍，如触觉麻醉和机械异常性疼痛。哺乳动物如何感知轻触一直是科学界最大的谜团之一。这种知识的缺乏阻碍了预防或治疗机械感觉功能障碍的潜在有效方法的发展。我们的长期目标是揭示哺乳动物轻触感的细胞和分子机制。作为我们长期目标的第一阶段，本应用程序的总体目标是研究默克尔细胞-神经突复合体的机械转导机制，这是哺乳动物感知光触摸所必需的感觉结构。我们的中心假设是，默克尔细胞是表达机械活化离子通道（MA）的机械换能器细胞，这些通道的激活触发默克尔细胞激发动作电位并释放兴奋性递质。这一假设是基于我们使用我们最近开发的来自胡须毛囊中的默克尔细胞的膜片钳记录（默克尔细胞原位膜片钳技术）获得的初步结果。这项创新技术首次使我们成功地记录了默克尔细胞的毫安电流。我们进一步发现，默克尔细胞在对机械刺激的反应中产生动作电位。我们在默克尔细胞原位膜片钳记录技术方面的独特专业知识使我们处于领先地位，可以通过以下具体目标来测试假设：1)阐明激活默克尔细胞的毫安电流的离子机制，并表征默克尔细胞的毫安通道特性；2) Merkel细胞中编码机械活动的身份离子通道；3)描述默克尔细胞传递机械活动的机制。上述研究结果将在细胞和分子水平上提供关于光触觉的科学知识。该研究可能具有临床意义，从糖尿病和其他疾病的感觉功能障碍到默克尔细胞功能障碍，如默克尔细胞癌。

DESCRIPTION (provided by applicant): The sense of light touch is critically important for daily life but this important sense can be altered to result in sensory dysfunctions such as tactile anesthesia and mechanical allodynia under pathological conditions. How mammals can sense light touch has been one of the biggest mysteries in science. This lack of knowledge prevents development of potentially effective approaches for preventing or treating mechanical sensory dysfunctions. Our long-term-goal is to uncover the cellular and molecular mechanisms underlying the sense of light touch in mammals. As the first stage of our long-term goal, the overall objective of this application is to study mechanisms underlying mechanical transduction of Merkel cell-neurite complex, a sensory structure essential for sensing light touch in mammals. Our central hypothesis is that Merkel cells are mechanical transducer cells that express mechanically activated ion channels (MA) and that activation of these channels triggers Merkel cells to fire action potentials and release excitatory transmitters. This hypothesis is based on ou preliminary results obtained by using our recently developed patch-clamp recordings from Merkel cells situated in whisker hair follicles (Merkel cell in situ patch-clamp technique). This innovative technique has, for the first time, led us to successfully record MA currents from Merkel cells. We have further discovered that Merkel cells in situ fire action potentials in response to mechanical stimulation. Our unique expertise of Merkel cell in situ patch-clamp recording technique places us at an advanced position to test the hypothesis with the following specific aims: 1) Elucidate ionic mechanisms of MA currents that excite Merkel cells in situ and characterize Merkel cell MA channel properties; 2) Identity ion channels that encode mechanical activity in Merkel cells; and 3) Delineate the mechanisms underlying the transmission of mechanical activity by Merkel cells. The outcomes of the above investigations will provide scientific knowledge about the sense of light touch at a cellular and molecular level. The study may have clinical implications ranging from sensory dysfunctions seen in diabetes and other disease conditions to Merkel cell malfunctions such as Merkel cell carcinoma.