Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of K_v1.3 and K_Ca3.1 Channels in T Cells

Abstract

N-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca²⁺ mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of K_v1.3 and K_Ca3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that K_v1.3 and K_Ca3.1 channels are their major effectors.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01273-13.

ACKNOWLEDGMENTS

We thank G. Weitz for technical assistance, M. Gunzer for DC culture reagents and mice, and E. Serfling for mice and discussion.

N.S. and T.B. were supported by grant SFB854-TP9 from the Deutsche Forschungsgemeinschaft (DFG) to M.H. and U.B.

U.B. and M.H. designed the study and analyzed and discussed the data. S.K., N.S., J.M., T.L., T.B., and U.B. performed experiments and analyzed data. S.K.-H. provided NFATc1-EGFP mice, and R.S. provided GluN1^flx/flx × Cre deleter mice. B.S. contributed reagents and discussion. M.H. and U.B. wrote the manuscript.

We declare that we have no conflicts of interest.