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

哺乳动物光触觉的细胞和离子通道机制

• 批准号: 8690017
• 负责人: JIANGUO GU
• 金额: $ 3.58万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-10-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690017
• 关键词: Action Potentials; Anesthesia procedures; Cell membrane; Cell physiology; Cells; Clinical; Complex; Data; Development; Diabetes Mellitus; Discrimination; Disease; Epidermis; Fiber; Fingers; Fire - disasters; Functional disorder; Gated Ion Channel; Goals; Hair follicle structure; Human; In Situ; Investigation; Ion Channel; Knowledge; Lead; Life; Light; Lip structure; Mammals; Measures; Mechanical Stimulation; Mechanics; Mediating; Membrane; Merkel Cells; Merkel cell carcinoma; Molecular; Neurites; Organ; Outcome; Pain; Patch-Clamp Techniques; Positioning Attribute; Property; Research; Science; Sensory; Shapes; Signal Transduction; Staging; Structure; Synapses; Tactile; Techniques; Testing; Texture; Time; Touch sensation; Transducers; Vibrissae; base; chemotherapy; innovation; mechanical allodynia; patch clamp; prevent; public health relevance; response; transmission process; vibration; voltage

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.

描述(申请人提供)：光触摸的感觉对日常生活至关重要，但这种重要的感觉可能会改变，导致感觉功能障碍，如触觉麻醉和病理条件下的机械性痛觉异常。哺乳动物如何感觉到光的触摸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光触觉的细胞和分子机制。作为我们长期目标的第一阶段，这项应用的总体目标是研究Merkel细胞-轴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一种感觉结构。我们的中心假设是，Merkel细胞是表达机械激活离子通道(MA)的机械传导细胞，这些通道的激活触发Merkel细胞发射动作电位并释放兴奋性递质。这一假说是基于我们最近开发的位于胡须毛囊中的Merkel细胞的膜片钳记录(Merkel细胞原位膜片钳技术)获得的初步结果。这项创新的技术首次使我们成功地记录了默克尔细胞的MA电流。我们进一步发现，Merkel细胞对机械刺激的反应是原位的动作电位。我们在Merkel细胞原位膜片钳记录技术方面的独特专业技术使我们处于领先地位，以检验这一假说，具体目的如下：1)阐明激发Merkel细胞的MA电流的离子机制，并表征Merkel细胞的MA通道特性；2)编码Merkel细胞机械活动的相同离子通道；以及3)描述Merkel细胞机械活动传递的潜在机制。上述研究的结果将在细胞和分子水平上提供关于光触觉的科学知识。这项研究可能具有临床意义，从糖尿病和其他疾病中出现的感觉障碍到默克尔细胞功能障碍，如默克尔细胞癌。