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J. Biol. Chem., Vol. 281, Issue 4, 1897-1904, January 27, 2006

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Genetic Demonstration That the Plasma Membrane Maxianion Channel and Voltage-dependent Anion Channels Are Unrelated Proteins^*

Ravshan Z. Sabirov1, Tatiana Sheiko, Hongtao Liu, Defeng Deng, Yasunobu Okada, and William J. Craigen

From the Department of Cell Physiology, National Institute for Physiological Sciences and Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8585, Japan and the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

The maxianion channel is widely expressed in many cell types, where it fulfills a general physiological function as an ATP-conductive gate for cell-to-cell purinergic signaling. Establishing the molecular identity of this channel is crucial to understanding the mechanisms of regulated ATP release. A mitochondrial porin (voltage-dependent anion channel (VDAC)) located in the plasma membrane has long been considered as the molecule underlying the maxianion channel activity, based upon similarities in the biophysical properties of these two channels and the purported presence of VDAC protein in the plasma membrane. We have deleted each of the three genes encoding the VDAC isoforms individually and collectively and demonstrate that maxianion channel (400 picosiemens) activity in VDAC-deficient mouse fibroblasts is unaltered. The channel activity is similar in VDAC1/VDAC3-double-deficient cells and in double-deficient cells with the VDAC2 protein depleted by RNA interference. VDAC deletion slightly down-regulated, but never abolished, the swelling-induced ATP release. The lack of correlation between VDAC protein expression and maxianion channel activity strongly argues against the long held hypothesis of plasmalemmal VDAC being the maxianion channel.

Received for publication, August 29, 2005 , and in revised form, October 24, 2005.

^* This work was supported by Grants-in-Aid for Scientific Research A and C (to Y. O. and R. Z. S.) from the MEXT of Japan, by MOD Grants 323 and R01 NS42319 (to W. J. C.), and the Child Health Research Center and Mental Retardation and Developmental Disabilities Research Center at Baylor College of Medicine. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan. Tel.: 81-564-55-7733; Fax: 81-564-55-7735; E-mail: sabirov{at}nips.ac.jp.

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