title: Immunosuppression by N-methyl-D-aspartate receptor antagonists is mediated through inhibition of Kv1.3 and KCa3.1 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 Ca(2+) 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 Kv1.3 and KCa3.1 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 Kv1.3 and KCa3.1 channels are their major effectors.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Kahlfuß
authors.forename: Narasimhulu
authors.initials: N
authors.lastname: Simma
authors.forename: Judith
authors.initials: J
authors.lastname: Mankiewicz
authors.forename: Tanima
authors.initials: T
authors.lastname: Bose
authors.forename: Theresa
authors.initials: T
authors.lastname: Lowinus
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein-Hessling
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.forename: Martin
authors.initials: M
authors.lastname: Heine
authors.forename: Ursula
authors.initials: U
authors.lastname: Bommhardt
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: C121673:Gprin1 protein, mouse; D007378:Interleukins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D051664:Kv1.3 Potassium Channel; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016194:Receptors, N-Methyl-D-Aspartate; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt