NITRIC OXIDE AND ION CHANNELS IN VASCULAR SMOOTH MUSCLE

描述：(摘自摘要)一氧化氮(NO)被认为是 通过刺激鸟苷环化酶来松弛平滑肌细胞， 其产物cGMP的积累及其对几种cGMP的依赖修饰 通过cGMP依赖的蛋白激酶的细胞内过程，包括 钙依赖钾通道(K+Ca)的激活与L型钙通道的抑制 钙离子通道。最近，我们展示了一种新的NO诱导途径 CGMP介导的正常兔主动脉非依赖性舒张作用 NO对K+Ca的直接作用。新鲜分散的兔主动脉SMC也 有延迟整流(K+DR)通道，是否有K+Ca通道尚不清楚 是NO直接作用的唯一靶点。我的初步数据显示 NO抑制激动剂诱导的二氢吡啶不敏感的钙内流 以不依赖于cGMP的方式进入SMC。我发现小(3 PS) 钙离子传导非选择性阳离子通道(和相应的 全细胞电流)，它可以被激动剂激活，并被 不是和镍，但不是硝苯地平。这些渠道可以调解 激动剂诱导的正常SMC内钙内流及NO对其影响。主 提出的假说是K+Ca、K+DR、L型钙离子和 非选择性阳离子通道介导cGMP非依赖性NO诱导 SMC细胞内钙的减少(和松弛)并发挥中枢作用 在这些过程中扮演的角色。总体目标是描述这两部小说的特点 通道介导的cGMP非依赖性NO诱导的SMC松弛途径。 其中一条途径始于不依赖cGMP的直接激活K+ 通道和通道膜超极化可抑制钙离子内流 L型钙通道。另一种途径可以通过NO的抑制来介导。 抑制钙离子内流的非选择性阳离子通道 降低细胞内钙离子浓度。我建议确定不同的 这些直接通路背后的机制，它们的功能作用和 相对重要性，与cGMP间接介导的作用进行比较 当然不是。

DESCRIPTION: (adapted from the abstract) Nitric oxide (NO) is thought to relax smooth muscle cells (SMC) by stimulation of guanylate cyclase, accumulation of its product cGMP and cGMP-dependent modification of several intracellular processes via cGMP-dependent protein kinase, including activation of Ca2+-dependent K+ channels (K+ Ca) and inhibition of L-type Ca2+ channels. Recently, we showed a novel pathway for NO-induced cGMP-independent relaxation of normal rabbit aorta which is mediated by the direct effect of NO on K+ Ca. Freshly dispersed SMC from rabbit aorta also have delayed rectifier (K+dr) channels and it is not clear, if K+ Ca channel is the only target for the direct effect of NO. My preliminary data shows that NO inhibits agonist-induced dihydropyridine-insensitive Ca2+ influx into SMC in a cGMP-independent manner. I found small (3 pS) calcium-conducting nonselective cation channels (and corresponding whole-cell currents) which can be activated by agonist and are inhibited by NO and nickel, but not nifedipine. These channels could mediate agonist-induced Ca2+ influx and effect of NO on it in normal SMC. The main hypothesis of this proposal is that K+ Ca, K+ dr, L-type Ca2+ and nonselective cation channels mediate the cGMP-independent NO-induced decrease in intracellular calcium (and relaxation) of SMC and play a central role in these processes. The overall goal is to characterize the two novel channel-mediated pathways for cGMP-independent NO-induced SMC relaxation. One of these pathways starts with direct cGMP-independent activation of K+ channels and via membrane hyperpolarization can inhibit Ca2+ influx through L-type Ca2+ channels. Another pathway can be mediated by inhibition by NO of non-selective cation channels which will suppress Ca2+ influx into SMC and decrease intracellular Ca2+. I propose to determine the distinct mechanisms underlying these direct pathways, their functional role and relative importance, comparing them with the indirect cGMP-mediated effects of NO.