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ANESTHETIC PHARMACOLOGY

The Effects of Lidocaine on the Activity of Glutamate Transporter EAAT3: The Role of Protein Kinase C and Phosphatidylinositol 3-Kinase

Sang-Hwan Do, MD PhD^*, Hong-yu Fang, MD^*, Byung-Moon Ham, MD PhD, and Zhiyi Zuo, MD PhD^*

*Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia; and Department of Anesthesiology, Seoul National University College of Medicine and Clinical Research Laboratory, Seoul, Republic of Korea

Address correspondence and reprint requests to Dr. Zhiyi Zuo, Department of Anesthesiology, University of Virginia, 1 Hospital Dr., PO Box 800710, Charlottesville, VA 22908–0710. Address e-mail to zz3c{at}virginia.edu

Using two electrode voltage clamps, we investigated the effects of lidocaine on one type of glutamate transporter, EAAT3, and the role of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) in mediating the lidocaine effects. EAAT3 was expressed in Xenopus oocytes, and membrane currents were recorded after the application of L-glutamate (30 µM). Lidocaine increased glutamate-induced inward currents significantly at 2 concentrations (100 µM and 1 mM), but not at other concentrations. Lidocaine (100 µM) significantly increased the V_max, but not the K_m, of EAAT3 for glutamate compared with control. The action sites of lidocaine on EAAT3 seem to be intracellular, because only intracellularly injected QX314 (permanently charged lidocaine analog) increased the response. The combination of phorbol-12-myrisate-13-acetate, an activator of PKC, and lidocaine did not further increase the responses compared with phorbol-12-myrisate-13-acetate or lidocaine alone, although each of these three groups showed significantly bigger responses than controls. Three PKC inhibitors (staurosporine, calphostin C, and chelerythrine) did not affect the basal EAAT3 activity but abolished lidocaine-enhanced EAAT3 activity. Wortmannin (a specific PI3K inhibitor) inhibited EAAT3 basal activity and lidocaine-enhanced EAAT3 activity. Our results suggest that lidocaine enhances EAAT3 activity at certain concentrations and that PKC and PI3K may mediate these lidocaine effects.

IMPLICATIONS: By using the Xenopus oocyte expression system, we investigated the effects of lidocaine on a glutamate transporter (EAAT3). Our findings suggest that lidocaine enhances EAAT3 activity at certain concentrations and that protein kinase C and phosphatidylinositol 3-kinase may mediate these lidocaine effects.

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