Update on cellular expression and function of ANO1 channels in urethral smooth muscle

Urinary continence is maintained by the cooperation of smooth and striated muscles where urethral smooth muscle cell (USMC) contractions contribute to resting urethral tone during bladder filling, whereas striated muscle contracts in response to sudden abdominal pressure rises. Anoctamin-1 (ANO1), a calcium-activated chloride channel (CaCC), has been identified as a potential regulator of USMC excitability. This review evaluates recent advances in understanding the cellular expression profile and functional contributions of ANO1 to USMC activity, for which there are significant species-specific differences. Discrepancies in findings are often attributed to a lack of cell-specific markers to map ANO1 expression in different cells and potentially off-target effects of CaCC antagonists. In rabbits, ANO1 is localized in specialized interstitial cell of Cajal-like cells (ICC-LC) that provide a depolarizing stimulus to enhance USMC excitability and contractility. Conversely in mice, rats and sheep, ANO1 is expressed directly within USMC. Although early studies in multiple species using non-specific antagonists suggested that CaCCs were critical for urethral tone and agonist-evoked contractions, recent experiments utilizing more selective pharmacological tools (e.g. Ani9) and cell-specific optogenetic sensors to distinguish ICC-LC from USMC, indicate ANO1 may not significantly contribute to tone or neurotransmitter-evoked contractions under normal physiological conditions, at least in mice and pigs. Although abundantly expressed, ANO1's role in urethra remains elusive. Emerging evidence suggests functional importance may manifest during pathophysiological states, such as urinary infections or metabolic disorders. This review summarizes these recent findings and proposes experiments that might fully elucidate the role of ANO1 channels in urethral smooth muscle.