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

Pflugers Arch. 2010 Feb;459(3):485-97. doi: 10.1007/s00424-009-0745-0. Epub 2009 Oct 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoctamin-1
  • Bestrophins
  • Calcium / metabolism
  • Calcium Signaling / physiology
  • Cell Line
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Ion Channels
  • Macular Degeneration / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / metabolism*
  • Oocytes / cytology
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • RNA Interference
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2Y2
  • Xenopus laevis
  • p21-Activated Kinases / metabolism


  • ANO1 protein, human
  • Anoctamin-1
  • BEST1 protein, human
  • Best1 protein, mouse
  • Bestrophins
  • Chloride Channels
  • Eye Proteins
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Ion Channels
  • KCNN4 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • P2RY2 protein, human
  • P2ry2 protein, mouse
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y2
  • p21-Activated Kinases
  • Calcium