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J. Biol. Chem., Vol. 283, Issue 31, 21655-21667, August 1, 2008

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Nonenzymatic Proton Handling by Carbonic Anhydrase II during H⁺-Lactate Cotransport via Monocarboxylate Transporter 1^*

From the Abteilung für Allgemeine Zoologie, FB Biologie, Technische Universität Kaiserslautern, P. O. Box 3049, D-67653 Kaiserslautern, Germany

Carbonic anhydrase (CA) is a ubiquitous enzyme catalyzing the equilibration of carbon dioxide, protons, and bicarbonate. For several acid/base-coupled membrane carriers it has been shown that the catalytic activity of CA supports transport activity, an interaction coined "transport metabolon." We have reported that CA isoform II (CAII) enhances lactate transport activity of the monocarboxylate transporter isoform I (MCT1) expressed in Xenopus oocytes, which does not require CAII catalytic activity ( Becker, H. M., Fecher-Trost, C., Hirnet, D., Sültemeyer, D., and Deitmer, J. W. (2005) J. Biol. Chem. 280, 39882-39889[Abstract/Free Full Text] ). Coexpression of MCT1 with either wild type CAII or the catalytically inactive mutant CAII-V143Y similarly enhanced MCT1 activity, although injection of CAI or coexpression of an N-terminal mutant of CAII had no effect on MCT1 transport activity, demonstrating a specific, nonenzymatic action of CAII on lactate transport via MCT1. If the H⁺ gradient was set to dominate the rate of lactate transport by applying low concentrations of lactate at a high H⁺ concentration, the effect of CAII was largest. We tested the hypothesis of whether CAII helps to shuttle H⁺ along the inner face of the cell membrane by measuring the pH change with fluorescent dye in different areas of interest during focal lactate application. Intracellular pH shifts decayed from the focus of lactate application to more distant sites much less when CAII had been injected. We present a hypothetical model in which the effective movement of H⁺ into the bulk cytosol is increased by CAII, thus slowing the dissipation of the H⁺ gradient across the cell membrane, which drives MCT1 activity.

Received for publication, March 18, 2008 , and in revised form, June 3, 2008.

^* The work was supported by Deutsche Forschungsgemeinschaft Grant De 231/16-4) and Research Training Group Grant GRK 845. 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. Tel.: 49-0-631-205-2491; Fax: 49-0-631-205-3515; E-mail: h.becker{at}biologie.uni-kl.de.

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