ER-localized bestrophin 1 activates Ca²⁺-dependent ion channels TMEM16A and SK4 possibly by acting as a counterion channel

Bestrophins form Ca²⁺-activated Cl^- channels and regulate intracellular Ca²⁺ signaling. We demonstrate that bestrophin 1 is localized in the endoplasmic reticulum (ER), where it interacts with stromal interacting molecule 1, the ER-Ca²⁺ sensor. Intracellular Ca²⁺ transients elicited by stimulation of purinergic P2Y₂ receptors in HEK293 cells were augmented by hBestl. The p21-activated protein kinase Pak2 was found to phosphorylate hBestl, thereby enhancing Ca²⁺ signaling and activation of Ca²⁺ -dependent Cl^-(TMEM 16A) and K⁺ (SK4) channels. Lack of bestrophin 1 expression in respiratory epithelial cells of mBestl knockout mice caused expansion of ER cisterns and induced Ca²⁺ deposits. hBest1 is, therefore, important for Ca²⁺ handling of the ER store and may resemble the long-suspected counterion channel to balance transient membrane potentials occurring through inositol triphosphate (IP3)-induced Ca²⁺ release and store refill. Thus, bestrophin 1 regulates compartmentalized Ca²⁺ signaling that plays an essential role in Best macular dystrophy, inflammatory diseases such as cystic fibrosis, as well as proliferation.