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 language | English (US) |
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Pages (from-to) | 485-497 |
Number of pages | 13 |
Journal | Pflugers Archiv European Journal of Physiology |
Volume | 459 |
Issue number | 3 |
DOIs | |
State | Published - Feb 2010 |
Externally published | Yes |
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)