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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572165/
• 关键词: MaxiK channel; Smooth muscle; Gs-protein-coupled receptor; β1-subunit; Thromboxane A2; cAMP; Urinary bladder smooth muscle; Knockout mouse; 血管平滑筋; 気管平滑筋; IP受容体; β-アドレナリン受容体; G-蛋白; イベリオトキシン; β_2-アドレナリン受容体; cAMP; ノツクアウトマウス; )β_1-サブユニット

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通道是大型，电压依赖性和Ca^<2+> k^+通道。该通道几乎无处不在分布在包括光滑肌肉在内的哺乳动物组织中。 MaxiK activation mediates relaxations to a variety of physical 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和β3） - 肾上腺素受体和IP受体通过cAMP独立的途径以及cAMP依赖性途径引起。 INβ2-肾上腺素受体和IP受体介导的松弛，这两种机制都包括Maxik通道激活。用霍乱毒素和GTP类似物的电生理学和机械研究……更多的UE表明，与CAMP无关的松弛机制部分归因于GS蛋白的直接激活该通道。 Inβ3受体介导的放松，延迟的校正K^+通道，而不是Maxik频道占无与伦比的放松机制。4。在尿膀胱平滑肌中，Maxik通道被证明可以作为主要的负面反馈元素来限制细胞外Ca^<2+>通过影响这种肌肉摄影的肌肉摄影的产生的动作潜在配置。包括β1亚基活化剂在内的Maxik通道开启器可能是治疗泌尿膀胱功能障碍（例如经常排尿）的潜在有用的治疗方法。5。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+>的关键作用，以控制平滑肌机械活性，并表明GS-蛋白介导的直接通道调节的实质性贡献。在下一步中，我们计划使用β1-杀解的小鼠揭示MaxikChannelβ1-Subunit的物理，特别是注意平滑肌收缩物，例如血栓烷A2。较少的

项目成果

Nishimaru K, Tanaka Y, Tanaka H, Shigenobu K.: "Inhibition of agonist-induced positive inotropy by a selective Rho-associated kinase inhibitor, Y-27632."J.Pharmacol.Sci.. 92. 424-427 (2003)

Nishimaru K、Tanaka Y、Tanaka H、Shigenobu K.：“选择性 Rho 相关激酶抑制剂 Y-27632 对激动剂诱导的正性肌力的抑制。”J.Pharmacol.Sci.. 92. 424-427 (2003)

Tanaka H, Ishii T, Fujisaki R, Miyamoto Y, Tanaka Y, Aikawa T, Hirayama W, Kawanishi T, Shigenobu K: "Effect of manganese on guinea pig ventricle: initial depression and late augmentation of contractile force."Biol.Pharm.Bull.. 25(3). 323-326 (2002)

Tanaka H、Ishii T、Fujisaki R、Miyamoto Y、Tanaka Y、Aikawa T、Hirayama W、Kawanishi T、Shigenobu K：“锰对豚鼠心室的影响：初始抑制和晚期收缩力增强。”Biol.Pharm。

Nishimaru K, Tanaka Y, Tanaka H, Shigenobu K.: "Pharmacological evidence for involvement of phospholipase D, Protein kinase C, and sodium-calcium exchanger in α-adrenoceptor-mediated negative inotropy in adult mouse ventricle"J.Pharmacol.Sci.. 92・3. 196-2

Nishimaru K、Tanaka Y、Tanaka H、Shigenobu K.：“磷脂酶 D、蛋白激酶 C 和钠钙交换器参与成年小鼠心室 α-肾上腺素受体介导的负性肌力的药理学证据”J.Pharmacol。科学.92・3.196-2

Otauka K, Tanaka H, Horinouchi T, Koike K, Shigenobu K, Tanaka Y.: "Functional contribution of voltage-dependent and Ca^<2+> activated K^+ (BK_<Ca>) channels to the relaxation of guinea-pig aorta in response to natriuretio peptides"J. Smooth Muscle Res..

Otauka K、Tanaka H、Horinouchi T、Koike K、Shigenobu K、Tanaka Y.：“电压依赖性和 Ca^<2> 激活的 K^ (BK_<Ca>) 通道对豚鼠主动脉舒张的功能贡献

Horinouchi T, Tanaka Y, Koike K: "Function of β1-adrenoceptors and mRNA expression ofβ1-and β2-adrenoceptors in guinea-pig esophagus."Eur.J.Pharmacol.. 473(1). 79-82 (2003)

Horinouchi T、Tanaka Y、Koike K：“豚鼠食道中β1-肾上腺素受体的功能以及β1-和β2-肾上腺素受体的mRNA表达。”Eur.J.Pharmacol.. 473(1) (2003)。