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(Circulation Research. 2008;103:864.)
© 2008 American Heart Association, Inc.

Cellular Biology

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^*, Per Larsen^*, Elena V. Bouzinova, Aleksandra Rojek, Donna M. Briggs Boedtkjer, Veronika Golubinskaya, Finn Skou Pedersen, Christian Aalkjær, Holger Nilsson

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. Present address for V.G. and H.N.: Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.

Correspondence to V. V. Matchkov, Institute of Physiology and Biophysics, University of Aarhus, 8000 Aarhus C, Denmark. 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

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