Stretch-Dependent K+ channels in GI Smooth Muscles

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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.