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J. Biol. Chem., Vol. 280, Issue 23, 21706-21712, June 10, 2005

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Hypoxic Augmentation of Ca²⁺ Channel Currents Requires a Functional Electron Transport Chain^*

Stephen T. Brown, Jason L. Scragg¶, John P. Boyle, Kristin Hudasek, Chris Peers||, and Ian M. Fearon**

From the Department of Biology, McMaster University, 1280 Main St. West, Hamilton, Ontario L8S 4K1, Canada, School of Medicine, The University of Leeds, Leeds LS2 9JT, United Kingdom, and ^**Faculty of Life Sciences, The University of Manchester, G.38 Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom

The incidence of Alzheimer disease is increased following ischemic episodes, and we previously demonstrated that following chronic hypoxia (CH), amyloid (A) peptide-mediated increases in voltage-gated L-type Ca²⁺ channel activity contribute to the Ca²⁺ dyshomeostasis seen in Alzheimer disease. Because in certain cell types mitochondria are responsible for detecting altered O₂ levels we examined the role of mitochondrial oxidant production in the regulation of recombinant Ca²⁺ channel _1C subunits during CH and exposure to A-(1–40). In wild-type (⁺) HEK 293 cells expressing recombinant L-type _1C subunits, Ca²⁺ currents were enhanced by prolonged (24 h) exposure to either CH (6% O₂) or A-(1–40) (50 nM). By contrast the response to CH was absent in ⁰ cells in which the mitochondrial electron transport chain (ETC) was depleted following long term treatment with ethidium bromide or in ⁺ cells cultured in the presence of 1 µM rotenone. CH was mimicked in ⁰ cells by the exogenous production of . by xanthine/xanthine oxidase. Furthermore A-(1–40) enhanced currents in ⁰ cells to a degree similar to that seen in cells with an intact ETC. The antioxidants ascorbate (200 µM) and Trolox (500 µM) ablated the effect of CH in ⁺ cells but were without effect on A-(1–40)-mediated augmentation of Ca²⁺ current in ⁰ cells. Thus oxidant production in the mitochondrial ETC is a critical factor, acting upstream of amyloid peptide production in the up-regulation of Ca²⁺ channels in response to CH.

Received for publication, March 22, 2005 , and in revised form, April 6, 2005.

^* Equipment was provided by New Opportunities grants (to I. M. F.) from the Canada Foundation for Innovation (Grant 7400) and the Ontario Innovation Trust. 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.

^¶ Supported by the British Heart Foundation.

^|| Supported by the British Heart Foundation, The Medical Research Council, The Alzheimer's Research Trust, and the Alzheimer's Society.

Supported by Grant-in-aid NA 5230 from the Heart and Stroke Foundation of Ontario. To whom correspondence should be addressed. Tel.: 44-161-275-5496; Fax: 44-161-275-5600; E-mail: ian.fearon{at}manchester.ac.uk.

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