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J. Biol. Chem., Vol. 281, Issue 50, 38133-38138, December 15, 2006

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Critical Role of Serine 465 in Isoflurane-induced Increase of Cell-surface Redistribution and Activity of Glutamate Transporter Type 3^*

From the Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908

Glutamate transporters (also called excitatory amino acid transporters, EAATs) bind extracellular glutamate and transport it to intracellular space to regulate glutamate neurotransmission and to maintain extracellular glutamate concentrations below neurotoxic levels. We previously showed that isoflurane, a commonly used anesthetic, enhanced the activity of EAAT3, a major neuronal EAAT. This effect required a protein kinase C (PKC) -dependent EAAT3 redistribution to the plasma membrane. In this study, we prepared COS7 cells stably expressing EAAT3 with or without mutations of potential PKC phosphorylation sites in the putative intracellular domains. Here we report that mutation of threonine 5 or threonine 498 to alanine did not affect the isoflurane effects on EAAT3. However, the mutation of serine 465 to alanine abolished isoflurane-induced increase of EAAT3 activity and redistribution to the plasma membrane. The mutation of serine 465 to aspartic acid increased the expression of EAAT3 in the plasma membrane and also abolished the isoflurane effects on EAAT3. These results suggest an essential role of serine 465 in the isoflurane-increased EAAT3 activity and redistribution and a direct effect of PKC on EAAT3. Consistent with these results, isoflurane induced an increase in phosphorylation of wild type, T5A, and T498A EAAT3, and this increase was absent in S465A and S465D. Our current results, together with our previous data that showed the involvement of PKC in the isoflurane effects on EAAT3, suggest that the phosphorylation of serine 465 in EAAT3 by PKC mediates the increased EAAT3 activity and redistribution to plasma membrane after isoflurane exposure.

Received for publication, April 24, 2006 , and in revised form, October 2, 2006.

^* This work was supported by National Institutes of Health Grants RO1 GM065211 and RO1 NS045983 (to Z. Z.). 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 Anesthesiology, University of Virginia Health System, P.O. Box 800710, One Hospital Dr., Charlottesville, VA 22908-0710. Tel.: 434-924-2283; Fax: 434-982-0019; E-mail: zz3c{at}virginia.edu.

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