TMEM16A channel signalling microdomains in the regulation of vascular function

Among the various chloride channel subtypes expressed in vascular tissues, Ca²⁺-activated chloride channels (CaCCs) have been most extensively studied for their critical role in linking intracellular Ca²⁺ signalling to changes in membrane potential. In vascular smooth muscle cells (SMCs), chloride is the predominant intracellular anion. Activation of chloride channels promotes chloride efflux, which leads to membrane depolarization, increased Ca²⁺ influx and, ultimately, vasoconstriction. The transmembrane protein TMEM16A is the primary mediator of classical CaCC conductance in vascular SMCs and plays a key role in regulating vasoconstriction. Recent studies have also underscored the importance of spatially localized Ca²⁺ signalling microdomains in regulating vascular function. Although most studies have focused on microdomains involving Ca²⁺ and K⁺ channels, TMEM16A-containing microdomains remain relatively underexplored. In this review, we synthesize current knowledge on TMEM16A-containing Ca²⁺ signalling microdomains in vascular smooth muscle and endothelium, summarize their physiological roles and discuss emerging evidence for additional TMEM16A-containing microdomains that may contribute to vascular regulation.