Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland.
Am J Physiol Renal Physiol. 2021 Apr 1;320(4):F525-F536. doi: 10.1152/ajprenal.00520.2020. Epub 2021 Feb 8.
Urinary continence is maintained in the lower urinary tract by the contracture of urethral sphincters, including smooth muscle of the internal urethral sphincter. These contractions occlude the urethral lumen, preventing urine leakage from the bladder to the exterior. Over the past 20 years, research on the ionic conductances that contribute to urethral smooth muscle contractility has greatly accelerated. A debate has emerged over the role of interstitial cell of Cajal (ICC)-like cells in the urethra and their expression of Ca-activated Cl channels encoded by anoctamin-1 [Ano1; transmembrane member 16 A () gene]. It has been proposed that Ano1 channels expressed in urethral ICC serve as a source of depolarization for smooth muscle cells, increasing their excitability and contributing to tone. Although a clear role for Ano1 channels expressed in ICC is evident in other smooth muscle organs, such as the gastrointestinal tract, the role of these channels in the urethra is unclear, owing to differences in the species (rabbit, rat, guinea pig, sheep, and mouse) examined and experimental approaches by different groups. The importance of clarifying this situation is evident as effective targeting of Ano1 channels may lead to new treatments for urinary incontinence. In this review, we summarize the key findings from different species on the role of ICC and Ano1 channels in urethral contractility. Finally, we outline proposals for clarifying this controversial and important topic by addressing how cell-specific optogenetic and inducible cell-specific genetic deletion strategies coupled with advances in Ano1 channel pharmacology may clarify this area in future studies. Studies from the rabbit have shown that anoctamin-1 (Ano1) channels expressed in urethral interstitial cells of Cajal (ICC) serve as a source of depolarization for smooth muscle cells, increasing excitability and tone. However, the role of urethral Ano1 channels is unclear, owing to differences in the species examined and experimental approaches. We summarize findings from different species on the role of urethral ICC and Ano1 channels in urethral contractility and outline proposals for clarifying this topic using cell-specific optogenetic approaches.
在泌尿系统中，尿道括约肌的收缩（包括尿道内括约肌的平滑肌）维持尿失禁。这些收缩会阻塞尿道腔，防止尿液从膀胱漏到体外。在过去的 20 年中，对导致尿道平滑肌收缩的离子电导的研究大大加快。关于 Cajal 间质细胞（ICC）样细胞在尿道中的作用及其表达钙激活氯离子通道的争论已经出现，这些氯离子通道由 anoctamin-1 [Ano1；跨膜成员 16A（）基因]编码。有人提出，尿道 ICC 中表达的 Ano1 通道可作为平滑肌细胞去极化的来源，增加其兴奋性并有助于产生张力。尽管在其他平滑肌器官（如胃肠道）中，ICC 中表达的 Ano1 通道的作用很明显，但由于不同研究组使用的物种（兔子、大鼠、豚鼠、绵羊和小鼠）和实验方法不同，这些通道在尿道中的作用尚不清楚。阐明这种情况的重要性是显而易见的，因为有效的靶向 Ano1 通道可能会导致治疗尿失禁的新方法。在这篇综述中，我们总结了不同物种关于 ICC 和 Ano1 通道在尿道收缩中的作用的关键发现。最后，我们概述了通过解决细胞特异性光遗传学和诱导型细胞特异性基因缺失策略与 Ano1 通道药理学的进展相结合如何澄清这一有争议和重要的课题，以澄清这一领域的未来研究。来自兔子的研究表明，尿道 Cajal 间质细胞（ICC）中表达的 anoctamin-1（Ano1）通道可作为平滑肌细胞去极化的来源，增加兴奋性和张力。然而，由于研究的物种和实验方法的不同，尿道 Ano1 通道的作用尚不清楚。我们总结了不同物种关于尿道 ICC 和 Ano1 通道在尿道收缩中的作用的发现，并提出了使用细胞特异性光遗传学方法澄清这一主题的建议。
