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Originally published In Press as doi:10.1074/jbc.M202763200 on May 24, 2002

J. Biol. Chem., Vol. 277, Issue 34, 30991-30997, August 23, 2002
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Changes in Glucose Transport and Water Permeability Resulting from the T310I Pathogenic Mutation in Glut1 Are Consistent with Two Transport Channels per Monomer*

Pavel IserovichDagger §, Dong Wang§, Li MaDagger ||, Hong Yang, Felipe A. ZunigaDagger , Juan M. Pascual, Kunyan KuangDagger , Darryl C. De Vivo, and Jorge FischbargDagger **Dagger Dagger

From the Departments of Dagger  Ophthalmology, ** Physiology and Cellular Biophysics, and  Neurology, Columbia University, New York, New York, 10032

We studied glucose and water passage across wild type (WT) glucose transporter Glut1 and its T310I pathogenic mutant, expressing them in Xenopus laevis oocytes. We found that the T310I mutation produced a 8-fold decrease in glucose transport (zero-trans influx, 13 ± 2% compared with WT), accompanied by a 2.8-fold increase in the osmotic water permeability (Pf 280 ± 40% compared with WT), and no change in the diffusional water permeability (Pd). The dependence of glucose and water transports on the amounts of mutant cRNA injected was identical exponential buildups (k = 19.7 ng), suggesting that they depend similarly on the quaternary structure. The Ea values for Pf were 16 ± 0.4 (WT) and 11 ± 1 kcal mol-1 (T310I). We report for the first time that 10 mM D-glucose and L-glucose inhibit Pf by ~45% in the WT but not in the T310I mutant. In addition, 10 mM maltose reduces Pf (15-20%) in both cases. However, 5 mM L-glucose increased the Pf of T310I, consistent with a cooperative effect. These experimental observations and an analysis of our three-dimensional model strongly suggest the presence of two channels per Glut1 monomer, one of which can be blocked by the mutation T310I.

* This work was supported in part by National Institutes of Health, U. S. Public Health Service Grants EY08918 (to J. F.), NS01698, NS37949, and RR00645 (to D. C. D.), the Will and the Colleen Giblin Foundations (to D. C. D.), and Research to Prevent Blindness, Inc. (to J. F.).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.

§ Both authors contributed equally to this work.

|| Recipient of a Fight for Sight Fellowship.

Dagger Dagger To whom correspondence should be addressed: Dept. of Physiology, College of Physicians & Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-9092; Fax: 212-305-2461; E-mail: jf20@columbia.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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