Increased TMEM16A-Mediated Ca²⁺-Activated Cl⁻ Currents in Portal Vein Smooth Muscle Cells of Caveolin 1-Deficient Mice

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Ca²⁺-activated Cl⁻ (Cl_Ca) channels regulate membrane excitability and myogenic tone in vascular smooth muscles. TMEM16A-coding proteins are mainly responsible for functional Cl_Ca channels in vascular smooth muscles, including portal vein smooth muscles (PVSMs). Caveolae are cholesterol-rich and Ω-shaped invaginations on the plasma membrane that structurally contributes to effective signal transduction. Caveolin 1 (Cav1) accumulates in caveolae to form functional complexes among receptors, ion channels, and kinases. The present study examined the functional roles of Cav1 in the expression and activity of Cl_Ca channels in the portal vein smooth muscle cells (PVSMCs) of wild-type (WT) and Cav1-knockout (KO) mice. Contractile experiments revealed that the amplitude of spontaneous PVSM contractions was larger in Cav1-KO mice than WT mice. Under whole-cell patch-clamp configurations, Cl_Ca currents were markedly inhibited by 1 µM Ani9 (a selective TMEM16A Cl_Ca channel blocker) in WT and Cav1-KO PVSMCs. However, Ani9-sensitive Cl_Ca currents were significantly larger in Cav1-KO PVSMCs than in WT PVSMCs. Expression analyses showed that TMEM16A expression levels were higher in Cav1-KO PVSMs than in WT PVSMs. Therefore, the caveolar structure formed by Cav1 negatively regulates the expression and activity of TMEM16A-mediated Cl_Ca channels in vascular smooth muscle cells.