Stretch-Dependent K+ channels in GI Smooth Muscles

胃肠道（GI）的图尼卡肌层含有连续的平滑肌细胞层。消化过程中，随着食物和食糜通过胃肠道腔，胃肠道器官的直径发生显著变化。因此，个体肌细胞经历长度的显著变化，这可能影响膜电位、兴奋性和对激动剂刺激的反应性。虽然许多研究者认为平滑肌具有牵张依赖性收缩，但结肠肌的牵张并不引起明显的收缩反应。因此，收缩似乎不是许多GI中对拉伸的基本反应。 机关这可能是GI平滑肌的独特特征，其允许储库功能所需的体积扩张。因此，胃肠平滑肌细胞可能具有稳定膜电位并限制肠壁扩张期间兴奋性的离子电导。这可能是对拉伸的“肌源性反应”的一个重要方面，其促进胃肠道某些区域的储库功能，并防止干扰肠神经系统提供的节段性和/或蠕动运动的协调。我们的初步研究结果表明，这一过程涉及拉伸依赖性K*（SDK）通道表达的GI平滑肌细胞和Cajal间质细胞（ICC）。这些信道 提出通过响应于拉伸产生外向电流来提供必要的负反馈通路（稳定膜电位）。 在本提案中，我们针对以下具体目标。 目标1.平滑肌和ICC中SDK通道的分布、一般属性和规则是什么？ 目标2. SDK通道在调节膜电位和兴奋性中的生理作用是什么？ 目标3：负责胃肠道肌肉中SDK通道的分子种类是什么？ 本研究将证明胃肠道平滑肌中一类重要的新通道，可能参与膜电位和兴奋性的调节，并可能介导这些组织对神经递质的一些反应。

The tunica muscularis of the gastrointestinal (GI) tract contains continuous sheets of smooth muscle cells. The diameters of GI organs change dramatically during digestion as food and chyme pass through the GI lumen. As a result, individual myocytes experience dramatic changes in length, which may affect membrane potential, excitability and responsiveness to agonist stimulation. Although many investigators believe that smooth muscles exhibit stretch-dependent contraction, stretch of colonic muscles does not initiate an obvious contractile response. Therefore, contraction does not appear to be a basic response to stretch in many GI organs. This may be a unique feature of GI smooth muscle that allows for the volume expansion necessary for a reservoir function. Thus it is likely that cells of GI smooth muscles include ionic conductances(s) that stabilize membrane potential and limit excitability during distension of the bowel wall. This may be an important aspect of the "myogenic response" to stretch that facilitates the reservoir function of some regions of the GI tract and prevents interference in the coordination of segmental and/or peristaltic movement provided by the enteric nervous system. Our preliminary results suggest that this process involves stretch-dependent K* (SDK) channels expressed by GI smooth muscle cells and interstitial cells of Cajal (ICC). These channels are proposed to provide the necessary negative-feed back pathway (stabilizing the membrane potential) by generating outward current in response to stretch. In the present proposal we address the following specific aims. Aim 1. What is the distribution, general properties and regulations of SDK channels in smooth muscle and ICC? Aim 2. What is the physiological role of SDK channels in regulating membrane potential and excitability? Aim 3. What is the molecular species responsible for SDK channels in GI muscles? This study will demonstrate an important new class of channels in GI smooth muscles that may participate in the regulation of membrane potential and excitability and may mediate some of the response of these tissues to neurotransmitters.