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

Abstract

Bestrophins form Ca(2+)-activated Cl(-) channels and regulate intracellular Ca(2+) signaling. We demonstrate that bestrophin 1 is localized in the endoplasmic reticulum (ER), where it interacts with stromal interacting molecule 1, the ER-Ca(2+) sensor. Intracellular Ca(2+) transients elicited by stimulation of purinergic P2Y(2) receptors in HEK293 cells were augmented by hBest1. The p21-activated protein kinase Pak2 was found to phosphorylate hBest1, thereby enhancing Ca(2+) signaling and activation of Ca(2+)-dependent Cl(-) (TMEM16A) and K(+) (SK4) channels. Lack of bestrophin 1 expression in respiratory epithelial cells of mBest1 knockout mice caused expansion of ER cisterns and induced Ca(2+) deposits. hBest1 is, therefore, important for Ca(2+) handling of the ER store and may resemble the long-suspected counterion channel to balance transient membrane potentials occurring through inositol triphosphate (IP(3))-induced Ca(2+) release and store refill. Thus, bestrophin 1 regulates compartmentalized Ca(2+) signaling that plays an essential role in Best macular dystrophy, inflammatory diseases such as cystic fibrosis, as well as proliferation.

Activation of Ca2+‐activated Cl− channel ANO1 by localized Ca2+ signals

“…Specifically, they proposed that functional proximity of ANO1 to the ER‐localized IP 3 Rs is important for the activation of ANO1 channels by the G q/11 ‐ and PLC‐coupled purinergic P2Y receptors in HEK293 cells and oocytes (Barro‐Soria et al . 2010; Kunzelmann et al . 2012).…”

Anoctamin 6 is an essential component of the outwardly rectifying chloride channel

“…Western blot and Ca 2+ measurement procedures were described in the work by Barro-Soria et al (29). RT-PCR and analysis of cell volume was performed according to previous studies (15,23).…”

Best1 Shot Through the Eye—Structure, Functions and Clinical Implications of Bestrophin-1 Protein

“…like many anion channels and unlike many cation channels, Best1 is not very discriminating among permeate ions. Best1 protein is very permeable for hco 3 -, suggesting that it may be a hCo 3 -channel (10,43). interestingly, hco 3 -permeability is similar to that for cl -, suggesting that in physiological conditions at least part of the electrical current created from Best1 could result from transport of hco 3 -.…”

“…Best1 protein is very permeable for hco 3 -, suggesting that it may be a hCo 3 -channel (10,43). interestingly, hco 3 -permeability is similar to that for cl -, suggesting that in physiological conditions at least part of the electrical current created from Best1 could result from transport of hco 3 -. Some evidences suggests that hco 3 -and cl -ions are transported through the same pore of the channel (43).…”

“…chloride channels act not only on the plasma membrane, but also on the membrane of many cellular organelles. Some authors showed localization of Best1 on the membrane of different cellular compartments (3,55). these data are from experiments with transfected cells, thus intracellular localization of the protein could be an artifact resulting from the overexpression.…”