Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production
Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production
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DOI：
10.3390/ijms21124462
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发表时间：
2020-06-01
影响因子：
5.6
通讯作者：
Yao, Jian
中科院分区：
文献类型：
--
作者：
Hong, Jingru;Yao, Jian
连接蛋白半通道在细胞信号传导和行为控制中起重要作用。考虑到降低细胞外Ca2+，激活半通道的条件，是一个很好的特点，在肾小球细胞中的肾素刺激，我们，因此，测试了半通道的潜在影响，在调节肾素在AS 4.1肾素分泌细胞。降低细胞外Ca（2+）诱导半通道开放，这与cAMP信号通路激活和增加肾素产生有关。用抑制剂阻断半通道或用siRNA下调Cxs可消除cAMP途径的激活和肾素的升高。进一步分析表明腺苷酸环化酶抑制剂SQ 22536可阻断cAMP途径的激活，提示腺苷酸环化酶的作用。此外，在肾小管上皮细胞系NRK中也观察到半通道参与cAMP信号通路的活化。总的来说，我们的研究结果的特点是半通道开放作为一个目前尚未认识到的分子事件参与低钙引起的激活cAMP途径和肾素的生产。因此，我们的研究结果提供了新的机制的见解低钙启动的细胞反应。鉴于cAMP信号通路在控制多种细胞功能中的重要性，我们的研究结果还强调了Cx形成通道在各种病理生理情况下的重要性。
Connexin hemichannels play an important role in the control of cellular signaling and behaviors. Given that lowering extracellular Ca2+, a condition that activates hemichannels, is a well-characterized stimulator of renin in juxtaglomerular cells, we, therefore, tested a potential implication of hemichannels in the regulation of renin in As4.1 renin-secreting cells. Lowering extracellular Ca(2+)induced hemichannel opening, which was associated with cAMP signaling pathway activation and increased renin production. Blockade of hemichannels with inhibitors or downregulation of Cxs with siRNAs abrogated the activation of cAMP pathway and the elevation of renin. Further analysis revealed that cAMP pathway activation was blocked by adenylyl cyclase inhibitor SQ 22536, suggesting an implication of adenyl cyclase. Furthermore, the participation of hemichannels in the activation of the cAMP signaling pathway was also observed in a renal tubular epithelial cell line NRK. Collectively, our results characterized the hemichannel opening as a presently unrecognized molecular event involved in low Ca2+-elicited activation of cAMP pathway and renin production. Our findings thus provide novel mechanistic insights into the low Ca2+-initiated cell responses. Given the importance of cAMP signaling pathway in the control of multiple cellular functions, our findings also highlight the importance of Cx-forming channels in various pathophysiological situations.