Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo 409-3898, Japan.
Int J Mol Sci. 2020 Jun 23;21(12):4462. doi: 10.3390/ijms21124462.
Connexin hemichannels play an important role in the control of cellular signaling and behaviors. Given that lowering extracellular Ca, 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 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 Ca-elicited activation of cAMP pathway and renin production. Our findings thus provide novel mechanistic insights into the low Ca-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.
缝隙连接半通道在控制细胞信号和行为方面发挥着重要作用。鉴于降低细胞外 Ca2+（一种激活半通道的条件）是肾小球旁细胞中肾素的一种特征性刺激物，因此，我们检测了缝隙连接半通道在调节 As4.1 分泌肾素细胞中肾素的潜在作用。降低细胞外 Ca2+诱导半通道开放，这与 cAMP 信号通路激活和肾素生成增加有关。用抑制剂阻断半通道或用 siRNA 下调 Cxs 可阻断 cAMP 通路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 阻断了 cAMP 通路的激活，提示腺嘌呤核苷酸环化酶的参与。此外，在肾近端小管上皮细胞系 NRK 中也观察到缝隙连接半通道参与 cAMP 信号通路的激活。总之，我们的研究结果表明，半通道开放是低钙诱导 cAMP 通路激活和肾素生成的一个目前尚未被识别的分子事件。我们的研究结果为低钙引发的细胞反应提供了新的机制见解。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。
