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Pflügers Archiv - European Journal of Physiology

, Volume 459, Issue 3, pp 485–497 | Cite as

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 KunzelmannEmail author
Signaling and Cell Physiology

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 hBest1. The p21-activated protein kinase Pak2 was found to phosphorylate hBest1, thereby enhancing Ca2+ signaling and activation of Ca2+-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 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.

Keywords

Bestrophin Ca2+-activated Cl currents CaCC Ca2+-activated K+ currents SK4 TMEM16A Pak2 Purinergic receptors Endoplasmic reticulum ER Ca2+ store 

Abbreviations

hBest1

human bestrophin 1

CaCC

Ca2+-activated Cl channels

SK4

small conductance calcium-activated potassium channel type 4

TMEM16A

transmembrane protein 16A

ANO1

anoctamin 1

Pak2

p21-activated protein kinase

ER

endoplasmic reticulum

SERCA

sarcoendoplasmic reticulum calcium ATPase

Stim1

stromal interacting molecule 1

DIDS

4,4′-diisothio-cyanostilbene-2,2′-disulfonic acid

Notes

Acknowledgments

This study was supported by the grants DFG SFB699 A6/A7, DFG KU 756/8-2, and Else Kröner-Fresenius-Stiftung P36/05//A44/05. We are grateful for the technical expertise of Caio Toledo, Christine Meese, Karin Schadendorf, Helga Schmidt, and Uwe de Vries in performing the ultrastructural analysis. The Ca2+-sensitive GFP protein G-CaMP2 was kindly provided by Dr. J. Nakai, Wako City Saitama, Japan. We gratefully acknowledge the supply of the vmd2−/− mice by MERCK Research Laboratories (770 Sumneytown Pike, West Point, PA, USA).

Supplementary material

424_2009_745_MOESM1_ESM.pdf (104 kb)
Supplement 1 (PDF 103 kb).
424_2009_745_MOESM2_ESM.pdf (61 kb)
Supplement 2 (PDF 61.3 kb).

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • René Barro-Soria
    • 1
  • Fadi Aldehni
    • 1
  • Joana Almaça
    • 1
  • Ralph Witzgall
    • 2
  • Rainer Schreiber
    • 1
  • Karl Kunzelmann
    • 1
    Email author
  1. 1.Institut für PhysiologieUniversität RegensburgRegensburgGermany
  2. 2.Institut für AnatomieUniversität RegensburgRegensburgGermany

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