Published online before print September 5, 2008, doi: 10.1161/CIRCRESAHA.108.178517
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 18, 2006
Revised on July 16, 2008
Accepted on August 27, 2008
Bestrophin-3 (Vitelliform Macular Dystrophy 2–Like 3 Protein) Is Essential for the cGMP-Dependent Calcium-Activated Chloride Conductance in Vascular Smooth Muscle Cells
Vladimir V. Matchkov *;
From the Water and Salt Centre (V.V.M., E.V.B., D.M.B.B., V.G., C.A., H.N.), Institute of Physiology and Biophysics; Institute of Anatomy (A.R.); and Department of Molecular Biology and Interdisciplinary Nanoscience Center (P.L., F.S.P.), University of Aarhus, Denmark.
* To whom correspondence should be addressed. E-mail: vvm{at}fi.au.dk.
Although the biophysical fingerprints (ion selectivity, voltage-dependence, kinetics, etc) of Ca2+-activated Cl- currents are well established, their molecular identity is still controversial. Several molecular candidates have been suggested; however, none of them has been fully accepted. We have recently characterized a cGMP-dependent Ca2+-activated Cl- current with unique characteristics in smooth muscle cells. This novel current has been shown to coexist with a "classic" (cGMP-independent) Ca2+-activated Cl- current and to have characteristics distinct from those previously known for Ca2+-activated Cl- currents. Here, we suggest that a bestrophin, a product of the Best gene family, is responsible for the cGMP-dependent Ca2+-activated Cl- current based on similarities between the membrane currents produced by heterologous expressions of bestrophins and the cGMP-dependent Ca2+-activated Cl- current. This is supported by similarities in the distribution pattern of the cGMP-dependent Ca2+-activated Cl- current and bestrophin-3 (the product of Best-3 gene) expression in different smooth muscle. Furthermore, downregulation of Best-3 gene expression with small interfering RNA both in cultured cells and in vascular smooth muscle cells in vivo was associated with a significant reduction of the cGMP-dependent Ca2+-activated Cl- current, whereas the magnitude of the classic Ca2+-activated Cl- current was not affected. The majority of previous suggestions that bestrophins are a new Cl- channel family were based on heterologous expression in cell culture studies. Our present results demonstrate that at least 1 family member, bestrophin-3, is essential for a well-defined endogenous Ca2+-activated Cl- current in smooth muscles in the intact vascular wall.
Key words: bestrophins • calcium-activated chloride channel • cGMP • posttranscriptional regulation • vascular biology
Related Article:
- Simply the Best?: Identity of Vascular cGMP-Dependent Cl– Current Revealed
- Iain A. Greenwood
Circ. Res. 2008 103: 782-783.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  M. Boudes, C. Sar, A. Menigoz, C. Hilaire, M. O. Pequignot, A. Kozlenkov, A. Marmorstein, P. Carroll, J. Valmier, and F. Scamps Best1 Is a Gene Regulated by Nerve Injury and Required for Ca2+-Activated Cl- Current Expression in Axotomized Sensory Neurons J. Neurosci., August 12, 2009; 29(32): 10063 - 10071. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Hartzell, K. Yu, Q. Xiao, L.-T. Chien, and Z. Qu Anoctamin/TMEM16 family members are Ca2+-activated Cl\#8722; channels J. Physiol., May 15, 2009; 587(10): 2127 - 2139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. O'Driscoll, W. J. Hatton, H. R Burkin, N. Leblanc, and F. C. Britton Expression, localization, and functional properties of Bestrophin 3 channel isolated from mouse heart Am J Physiol Cell Physiol, December 1, 2008; 295(6): C1610 - C1624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Greenwood Simply the Best?: Identity of Vascular cGMP-Dependent Cl- Current Revealed Circ. Res., October 10, 2008; 103(8): 782 - 783. [Full Text] [PDF]
|
|