Orai storeoperated Ca2+ entry channels modulate urethral smooth muscle contractility.

In the European Union, urinary incontinence (UI) affects 45% of adults during their lifetime, representing a major clinical and socio-economic burden. Failure of urethral smooth muscle (USM) to contract normally (hypo or hypercontractility) contributes to UI symptoms such as urine leakage during bladder filling or inability to urinate due to obstruction. Adequate UI treatments are lacking, partially due to a lack in understanding of cellular mechanisms underlying USM contraction. USM contractions rely on Ca2+ signaling in urethral smooth muscle cells (USMC), resulting from Ca2+ release from internal stores and Ca2+ influx from extracellular sources, such as voltage-gated L-type Ca2+ channels or store-operated Ca2+ entry (SOCE) channels. L-type Ca2+ channel inhibitors have inconsistent effects on urethral contractions across species, including humans, and thus solely targeting this pathway may be insufficient to modulate USM contractility. Recent animal experiments suggest SOCE mediated by Orai-STIM proteins is a critical determinant of Ca2+ signaling in USMC, maintaining regenerative Ca2+ release from internal stores, and thus may be a targetable pathway for influencing USM contractility. In this review, we highlight evidence suggesting SOCE as critical for Ca2+ signaling in USMC from multiple species and propose possible mechanisms for how this occurs at the cellular level.