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Physiological roles of MaxiK channel in the regulation of smooth muscle mechanical activity and the new insights into the molecular mechanisms responsible for MaxiK channel-mediated responses

MaxiK 通道在平滑肌机械活动调节中的生理作用以及对 MaxiK 通道介导反应分子机制的新见解

基本信息

批准号：
14572165
负责人：
TANAKA Yoshio
金额：
$ 2.62万
依托单位：
Toho University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

1.MaxiK channel is the large-conductance, voltage-dependent and Ca^<2+> K^+ channel. This channel is almost ubiquitously distributed among mammalian tissues including smooth muscles. MaxiK activation mediates relaxations to a variety of physiological substances whereas its inhibition plays a significant role in contractile responses.2.In the present study, the roles of MaxiK channel in the regulation of smooth muscle mechanical activity and its molecular mechanisms were further investigated for our better understating of the channel, and we obtained the following new findings.3.Arterial and tracheal smooth muscle relaxations mediated through Gs-protein-coupled receptors such as β (β1, β2 andβ3)-adrenoceptors and IP receptor were elicited through cAMP-independent pathway as well as a cAMP-dependent route. Inβ2-adrenoceptor and IP-receptor-mediated relaxations, both mechanisms included MaxiK channel activation. Electrophysiological and mechanical studies with cholera toxin and GTP analog … More ues indicated that cAMP-independent relaxant mechanism is partly attributed to a direct activation of this channel by Gs-protein. Inβ3-receptor-mediated relaxation, delayed rectified K^+ channel but not MaxiK channel accounts for cAMP-independent relaxant mechanisms.4.In urinary bladder smooth muscle, MaxiK channel was demonstrated to function as a primary negative feedback element to limit extracellular Ca^<2+> influx through affecting action potential configurations in the generation of this muscle spontaneous myogenic contraction. MaxiK channel openers including β1-subunit activators may be a potentially useful therapeutic remedy for the treatment of urinary bladder dysfunctions such as frequent urination.5.These results support the key role of MaxiK channel as a rheostat fine tuning membrane potential and intracellular Ca^<2+> to control smooth muscle mechanical activity and indicate the substantial contribution of Gs-protein-mediated direct channel regulation. In the next step, we are planning to reveal the physiological of MaxiK channelβ1-subunit usingβ1-subunit-deleted mice with paying attention especially to smooth muscle constrictors such as thromboxane A2. Less

1. MaxiK通道是一种大电导、电压依赖性的Ca^2+-K^+通道。该通道几乎普遍分布在哺乳动物组织中，包括平滑肌。MaxiK通道的激活可介导对多种生理物质的舒张反应，而抑制MaxiK通道则在收缩反应中起重要作用。2.为了更好地了解MaxiK通道，本研究进一步探讨了MaxiK通道在平滑肌机械活动调节中的作用及其分子机制。3.通过Gs蛋白偶联受体如β受体介导的动脉和气管平滑肌舒张（β1、β2和β3）-肾上腺素能受体和IP受体通过cAMP非依赖性途径和cAMP依赖性途径被激发。在β2肾上腺素受体和IP受体介导的舒张中，两种机制均包括MaxiK通道激活。霍乱毒素和GTP类似物的电生理和力学研究 ...更多信息结果表明，cAMP非依赖性舒张机制部分归因于GS蛋白直接激活该通道。在β3-受体介导的舒张中，延迟整流钾通道而非MaxiK通道是cAMP非依赖性舒张机制。4.在膀胱平滑肌中，MaxiK通道被证明是一个主要的负反馈元件，通过影响动作电位构型来限制细胞外Ca^2+内流。MaxiK通道开放剂包括β1亚基激活剂可能是治疗膀胱功能障碍如频繁排尿的潜在有用的治疗药物。这些结果支持MaxiK通道作为变阻器微调膜电位和细胞内Ca^2+来控制平滑肌机械活动的关键作用，并表明Gs蛋白介导的直接通道调节的重要贡献。下一步，我们计划使用β1-亚基缺失小鼠揭示MaxiK通道β1-亚基的生理学，特别关注平滑肌收缩剂如血栓素A2。少