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J Biol Chem, Vol. 275, Issue 9, 6302-6307, March 3, 2000

Kinetic and Pharmacological Properties of Human Brain Na+/H+ Exchanger Isoform 5 Stably Expressed in Chinese Hamster Ovary Cells*

Elöd Z. SzabóDagger , Masayuki NumataDagger , Gary E. Shull§, and John OrlowskiDagger

From the Dagger  Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada and the § Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267-0524

The recently cloned Na+/H+ exchanger isoform 5 (NHE5) is expressed predominantly in brain, yet little is known about its functional properties. To facilitate its characterization, a full-length cDNA encoding human NHE5 was stably transfected into NHE-deficient Chinese hamster ovary AP-1 cells. Pharmacological analyses revealed that H+i-activated 22Na+ influx mediated by NHE5 was inhibited by several classes of drugs (amiloride compounds, 3-methylsulfonyl-4-piperidinobenzoyl guanidine methanesulfonate, cimetidine, and harmaline) at half-maximal concentrations that were intermediate to those determined for the high affinity NHE1 and the low affinity NHE3 isoforms, but closer to the latter. Kinetic analyses showed that the extracellular Na+ dependence of NHE5 activity followed a simple hyperbolic relationship with an apparent affinity constant (KNa) of 18.6 ± 1.6 mM. By contrast to other NHE isoforms, NHE5 also exhibited a first-order dependence on the intracellular H+ concentration, achieving half-maximal activation at pH 6.43 ± 0.08. Extracellular monovalent cations, such as H+ and Li+, but not K+, acted as effective competitive inhibitors of 22Na+ influx by NHE5. In addition, the transport activity of NHE5 was highly dependent on cellular ATP levels. Overall, these functional features distinguish NHE5 from other family members and closely resemble those of an amiloride-resistant NHE isoform identified in hippocampal neurons.

* This work was supported in part by Grant MT-11221 from the Medical Research Council of Canada (to J. O.) and by National Institutes of Health Grant DK50594 (to G. E. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a scientist award from the Medical Research Council of Canada. To whom correspondence should be addressed: Dept. of Physiology, McGill University, McIntyre Medical Science Bldg., 3655 Drummond St., Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-8335; Fax: 514-398-7452; E-mail: orlowski@med.mcgill.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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