The RyR-Cl_Ca -VDCC axis contributes to spontaneous tone in urethral smooth muscle

Current therapies including pharmaceutical intervention and surgery have limited efficacy on stress urinary incontinence (SUI). One type of SUI is due to low intraurethral pressure caused by the disabled contraction of urethral smooth muscle (USM). However, the molecular mechanisms underlying the motility of USM remain unknown. Here, we show that USM represents spontaneous tone after stretching in humans and mice. Deletion of TMEM16A in the smooth muscle of mice abolishes spontaneous urethral tone. Furthermore, Cl_Ca currents and [Ca²⁺ ]_i in TMEM16A^SMKO mice were largely impaired. Inhibitors of ryanodine receptor (RyR), TMEM16A encoded calcium-activated chloride channel (Cl_Ca ) and L-type voltage-dependent calcium channel (VDCC) fully prevented spontaneous tone accompanied by a significant decrease of intracellular calcium concentration ([Ca²⁺ ]_i ). In summary, RyR-Cl_Ca -VDCC signaling contributes to spontaneous USM tone. This finding may provide a new promising approach for women with stress SUI who reject surgery.