title: 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.
authors.affiliation: Institut für Physiologie, Universität Regensburg, Universitätsstrasse 31, 93053 Regensburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Barro-Soria
authors.forename: Fadi
authors.initials: F
authors.lastname: Aldehni
authors.forename: Joana
authors.initials: J
authors.lastname: Almaça
authors.forename: Ralph
authors.initials: R
authors.lastname: Witzgall
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D000075002:Bestrophins; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D007473:Ion Channels; D008268:Macular Degeneration / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2; D014982:Xenopus laevis; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; C113133:BEST1 protein, human; C491856:Best1 protein, mouse; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007473:Ion Channels; C496923:KCNN4 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C546385:P2RY2 protein, human; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D054462:p21-Activated Kinases; D002118:Calcium