NITRIC OXIDE AND ION CHANNELS IN VASCULAR SMOOTH MUSCLE

描述：（改编自摘要）一氧化氮（NO）被认为是 通过刺激鸟苷酸环化酶来松弛平滑肌细胞（SMC）， 其产物cGMP的积累和几种cGMP依赖性修饰 通过cGMP依赖性蛋白激酶的细胞内过程，包括 激活Ca 2+依赖性K+通道（K+ Ca）和抑制L型 Ca 2+通道 最近，我们发现了一种新的途径， 正常兔主动脉的cGMP非依赖性舒张是由 NO对K+ Ca的直接影响。新鲜分散的兔主动脉SMC也 有延迟整流（K+dr）通道，尚不清楚K+ Ca通道是否 是NO直接影响的唯一目标。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Ca 2+内流 以不依赖cGMP的方式进入SMC。 我发现小（3 pS） 钙传导非选择性阳离子通道（和相应的 全细胞电流），其可被激动剂激活并被 NO和镍，但不是硝苯地平。 这些通道可以介导 激动剂诱导的正常平滑肌细胞Ca ~（2+）内流及NO对其的影响。 主要 该假说认为K+ Ca，K+ dr，L型Ca ~（2+）， 非选择性阳离子通道介导cGMP非依赖性NO诱导的 平滑肌细胞内钙离子减少（和舒张），并发挥中枢 在这些过程中的作用。 总的目标是描述这两部小说 通道介导的cGMP非依赖性NO诱导的SMC松弛途径。 这些途径之一始于直接的cGMP非依赖性K+激活 通道和通过膜超极化可以抑制Ca 2+内流， L型钙通道。 另一个途径可以通过抑制NO介导 抑制钙离子流入SMC的非选择性阳离子通道 降低细胞内Ca ~（2+）。 我建议确定 这些直接途径的机制，其功能作用和 相对重要性，将其与间接cGMP介导的效应进行比较 号

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.