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ORIGINAL ARTICLE

Modulation of Voltage-Gated Potassium Channels in Human T Lymphocytes by Extracellular Glutamate

Department of Neurology, Laboratory of Experimental Neurophysiology, Medical School, University of Athens, Eginition Hospital, Athens, Greece

Abstract

Glutamate is present in the plasma under tightly regulated concentrations. However, under conditions of immune deficiency, such as AIDS and malignancy, its plasma levels are highly elevated. In vitro, glutamate interacts with T lymphocytes, affecting mitogen-induced calcium responses, whereas at high doses, it impairs T lymphocyte proliferation, a process strongly dependent on the activity of voltage-gated potassium channels. In this study, we demonstrate novel dose-related effects of the endogenous ligand glutamate and its metabotropic and non-N-methyl-D-aspartic acid receptor agonists on the electrophysiological properties of native K_v1.3 channels of human T lymphocytes. Glutamate, at concentrations within normal plasma levels, positively modulates K_v1.3 channel gating, causing currents to activate faster and at significantly more hyperpolarized potentials, hence rendering the T lymphocyte readily responsive to immune stimuli. This effect is maximal at 1 µM Glu and is fully mimicked by a 100 µM concentration of the metabotropic receptor agonist trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. Most importantly, Glu, at concentrations 100 µM, which in vitro produce suppression of mitogen-induced proliferation, significantly decreases whole-cell potassium currents by increasing current and steady-state inactivation. This effect saturates at 1000 µM and seems to result from the subsequent activation of low-affinity metabotropic Glu receptors, as suggested by specific agonist data. Therefore, the antiproliferative effects of high glutamate may, at least in part, result from its inhibitory effect on the potassium current, suggesting an in vivo immunosuppressive role of elevated plasma glutamate.

Address correspondence to: Dr. Cornelia Poulopoulou, Laboratory of Experimental Neurophysiology, Eginition Hospital, 72-74 Vas. Sophias Avenue, Athens, Greece. E-mail: cpoulop{at}med.uoa.gr

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