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

René Barro-Soria, Fadi Aldehni, Joana Almaça, Ralph Witzgall, Rainer Schreiber, Karl Kunzelmann

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)485-497
Number of pages13
JournalPflugers Archiv European Journal of Physiology
Volume459
Issue number3
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

Keywords

  • Bestrophin
  • Ca -activated K currents
  • Ca store
  • Ca-activated Cl currents
  • CaCC
  • ER
  • Pak2
  • Purinergic receptors endoplasmic reticulum
  • SK4
  • TMEM16A

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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