Inward Conductances in Regulation of Colon ic Excitability

结肠兴奋性调节中的内向传导

• 批准号: 8280399
• 负责人: SANG Don KOH
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8280399
• 关键词: Acetylcholine; Address; Affect; Agonist; Cations; Colon; Complex; Digestion; Enteral; Equilibrium; Event; Functional disorder; Gastrointestinal Motility; Gastrointestinal tract structure; Histamine Receptor; Human; Inflammation; Inflammatory Bowel Diseases; Instruction; Interstitial Cell of Cajal; Intestinal Motility; Investigation; Ion Channel; Knockout Mice; Mediator of activation protein; Membrane; Membrane Potentials; Microelectrodes; Molecular; Monkeys; Motor; Motor Activity; Motor Neurons; Mus; Muscle; Muscle Cells; Nerve; Pacemakers; Pathway interactions; Pattern; Physiological; Play; Potassium Channel; Property; Protein Family; Protein Isoforms; Regulation; Rest; Rho-associated kinase; Role; Second Messenger Systems; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; TRP channel; Testing; Work; cell motility; gastrointestinal; receptor; response; second messenger; voltage

The gastrointestinal tract mixes luminal contents and initiates the forward propulsion of luminal contents. This motor activity is regulated by both excitatory and inhibitory motor nerves as well as by pacemaker potentials generated by interstitial cells of Cajal (ICC). Smooth muscle cells serve as the final effectors of motor activity. Regardless of the commands issued by enteric motor neurons and ICC, if SM excitability mechanisms are not functioning properly motor dysfunction will result. The ionic conductances that regulate resting membrane potential in smooth muscle cells are of central importance in the regulation of Gl motility. The ionic mechanisms in the muscle play a fundamental role in setting the resting membrane potential and thus determining contractile activity. However, resting membrane potential is not determined solely by the activity of K+ channels. Inward currents, such as resting Na+ or Ca2+ conductance can shift the resting membrane potentials to values more positive than the K+ equilibrium potential. This 'leak' current is thought to be due to the expression of a variety of different non-selective cation channels (NSCC). Therefore the working hypothesis for this application is that NSCC, particularly the TRP family of proteins, play an important role in regulating RMP in colon and that the activity of these channels can be regulated by several different second messenger pathways or pathological conditions that alter contractile activity of the colonic muscle. Thus we will investigate the following specific aims. Aim 1. What are the electrophysiological properties of basally activated NSCC? Aim 2. What are the intracellular signaling mechanisms regulating basally activated NSCC? Aim 3. What are the molecular candidates for basally activated NSCC? Aim 4. What are the functional roles of basally activated NSCC in pathophysiological conditions? In summary investigation of these hypotheses will aid our understanding of functional role of basally activated NSCC in relation to regulation of the resting membrane potentials in physiological and pathological conditions. RELEVANCE (See instructions): Relevance to human inflammatory bowel disease

胃肠道混合腔内容物并启动腔内容物的向前推进。这 运动活动既受兴奋性和抑制性运动神经调节，也受起搏电位调节。 由Cajal间质细胞(ICC)产生。平滑肌细胞是运动活动的最终效应器。 无论肠运动神经元和ICC发出什么指令，如果SM兴奋机制不是 正常运作会导致运动功能障碍。调节静息膜的离子电导 在Gl运动的调节中，平滑肌细胞的潜伏期起着核心作用。《离子》 肌肉中的机制在设置静息膜电位中起着基础性作用，因此 测定收缩活动。然而，静息膜电位并不完全由活性决定。 K+通道。内向电流，如静息的Na+或Ca~(2+)电导，会使静息的细胞膜发生移动 电势比K+平衡电势更正的值。这种“泄漏”电流被认为是由于 表达多种不同的非选择性阳离子通道(NSCC)。因此，工作 这种应用的假设是，NSCC，特别是Trp蛋白家族，在 调节结肠中的RMP，这些通道的活动可以通过几个不同的秒来调节 改变结肠肌肉收缩活动的信使通路或病理状态。因此，我们将 调查以下具体目标。 目的1.碱激活NSCC的电生理特性是什么？ 目的2.调节碱性激活的NSCC的细胞内信号机制是什么？ 目的3.碱基激活NSCC的候选分子有哪些？ 目的4.碱性激活的NSCC在病理生理条件下的功能作用是什么？ 综上所述，对这些假说的研究将有助于我们理解碱性激活蛋白的功能作用。 NSCC与生理和病理条件下静息膜电位的调节有关。 相关性(请参阅说明)： 与人类炎症性肠病的相关性