Abstract
Several ion channels are thought to be directly modulated by nitric oxide (NO), but the molecular basis of this regulation is unclear. Here we show that the NMDA receptor (NMDAR)-associated ion channel was modulated not only by exogenous NO but also by endogenous NO. Site-directed mutagenesis identified a critical cysteine residue (Cys 399) on the NR2A subunit whose S-nitrosylation (NO+ transfer) under physiological conditions underlies this modulation. In cell systems expressing NMDARs with mutant NR2A subunits in which this single cysteine was replaced by an alanine, the effect of endogenous NO was lost. Thus endogenous S-nitrosylation can regulate ion channel activity.
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References
Hollmann, M. & Heinemann, S. F. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31– 108 (1994).
McBain, C. J. & Mayer, M. L. N-Methyl-d-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–760 (1994).
Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 ( 1988).
Meldrum, B. & Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 11, 379–387 (1990).
Dingledine, R., McBain, C. J. & McNamara, J. O. Excitatory amino acid receptors in epilepsy. Trends Pharmacol. Sci. 11, 334–338 (1990).
Lipton, S. A. & Rosenberg, P. A. Mechanisms of disease: Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994).
Manzoni, O. et al. Nitric oxide-induced blockade of NMDA receptors. Neuron 8, 653–662 ( 1992).
Lei, S. Z. et al. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 8, 1087–1099 (1992).
Hoyt, K. R., Tang, L.-H., Aizenman, E. & Reynolds, I. J. Nitric oxide modulates NMDA-induced increases in intracellular Ca2+ in cultured rat forebrain neurons. Brain Res. 592, 310–316 (1992).
Lipton, S. A. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993).
Manzoni, O. & Bockaert, J. Nitric oxide synthase activity endogenously modulates NMDA receptors. J. Neurochem. 61, 368–370 (1993).
Fagni, L., Olivier, M., Lafon-Cazal, M. & Bockaert, J. Involvement of divalent ions in the nitric oxide-induced blockade of N- methyl-D-aspartate receptors in cerebellar granule cells. Mol. Pharmacol. 47, 1239–1247 (1995).
Omerovic, A., Chen, S.-J., Leonard, J. P. & Kelso, S. R. Subunit-specific redox modulation of NMDA receptors expressed in Xenopus oocytes. J. Recept. Signal Transduct. Res. 15, 811–827 (1995).
Sucher, N. J., Awobuluyi, M., Choi, Y.-B. & Lipton, S. A. NMDA receptors: from genes to channels. Trends Pharmacol. Sci. 17, 348–355 ( 1996).
Stamler, J. S., Toone, E. J., Lipton, S. A. & Sucher, N. J. (S)NO signals: Translocation, regulation, and a consensus motif. Neuron 18, 691–696 ( 1997).
Bolotina, V. M., Najibi, S., Palacino, J. J., Pagaon, P. J. & Cohen, R. A. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368, 850–853 ( 1994).
Kurenny, D. E., Moroz, L. L., Turner, R. W., Sharkey, K. A. & Barnes, S. Modulation of ion channels in rod photoreceptors by nitric oxide. Neuron 13, 315–324 (1994).
Gaston, B. et al. Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro. J. Pharmacol. Exp. Ther. 268, 978–984 (1994).
Koivisto, A. & Nedergaard, J. Modulation of calcium-activated non-selective cation channel activity by nitric oxide in rat brown adipose tissue. J. Physiol. (Lond.) 486, 59– 65 (1995).
Koh, S. D., Campbell, J. D., Carl, A. & Sanders, K. M. Nitric oxide activates multiple potassium channels in canine colonic smooth muscle. J. Physiol. (Lond.) 489, 735– 743 (1995).
Campbell, D. L., Stamler, J. S. & Strauss, H. C. Redox modulation of L-type calcium channels in ferret ventricular myocytes. J. Gen. Physiol. 108, 277–293 (1996).
Broillet, M.-C. & Firestein, S. Direct activation of the olfactory cyclic nucleotide-gated channel through modulation of sulfhydryl groups by NO compounds. Neuron 16, 377– 385 (1996).
Takeuchi, T., Kishi, M., Ishii, T., Nishio, H. & Hata, F. Nitric oxide-mediated relaxation without concomitant changes in cyclic GMP content of rat proximal colon. Br. J. Pharmacol. 117, 1204–1208 ( 1996).
Yuan, X.-J., Tod, M. L., Rubin, L. J. & Blaustein, M. P. NO hyperpolarizes pulmonary artery smooth muscle cells and decreases the intracellular Ca2+ concentration by activating voltage-gated K+ channels. Proc. Natl. Acad. Sci. USA 93, 10489– 10494 (1996).
Xu, L., Eu, J. P., Meissner, G. & Stamler, J. S. Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 279, 234–237 (1998).
Kendrick, K. M. et al. NMDA and kainate-evoked release of nitric oxide and classical transmitters in the rat striatum: in vivo evidence that nitric oxide may play a neuroprotective role. Eur. J. Neurosci. 8, 1619–1634 (1996).
Lipton, S. A., Rayudu, P. V., Choi, Y.-B., Sucher, N. J. & Chen, H.-S. V. Redox modulation of the NMDA receptor by NO-related species. Prog. Brain Res. 118 , 73–82 (1998).
Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S. & Snyder, S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA 88, 6368–6371 ( 1991).
Dawson, V. L., Dawson, T. M., Bartley, D. A., Uhl, G. R. & Snyder, S. H. Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J. Neurosci. 13, 2651–2661 (1993).
Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P. & Lipton, S. A. Apoptosis and necrosis: two distinct events induced respectively by mild and intense insults with NMDA or nitric oxide/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. USA 92, 7162–7166 ( 1995).
Adamson, D. C. et al. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV–1 gp41. Science 274, 1917–1921 (1996).
Garthwaite, J., Charles, S. L. & Chess, W. R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385–388 ( 1988).
Bredt, D. S. & Snyder, S. H. Nitric oxide, a novel neuronal messenger. Neuron 8, 3– 11 (1992).
Shibuki, K. & Okada, D. Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 349, 326–328 (1991).
Akabas, M. H., Stauffer, D. A., Xu, M. & Karlin, A. Acetylcholine receptor channel structure probed in cysteine-substitution mutants. Science 258, 307–310 ( 1992).
Aizenman, E., Brimecombe, J. C., Potthoff, W. K. & Rosenberg, P. A. Why is the role of nitric oxide in NMDA receptor function and dysfunction so controversial? Prog. Brain Res. 118, 53–71 (1998).
Wo, Z. G. & Oswald, R. E. Transmembrane topology of two kainate receptor subunits revealed by N-glycosylation. Proc. Natl. Acad. Sci. USA 91, 7154– 7158 (1994).
Hollmann, M., Maron, C. & Heinemann, S. F. N-glycosylation site tagging suggests a three transmembrane domain topology for the glutamate receptor GluR1. Neuron 13, 1331–1343 ( 1994).
Wood, M. W., VanDongen, H. M. & VanDongen, A. M. Structural conservation of ion conduction pathways in K channels and glutamate receptors. Proc. Natl. Acad. Sci. USA 92, 4882–4886 ( 1995).
Armstrong, N., Sun, Y., Chen, G.-Q. & Gouaux, E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917 ( 1998).
Aizenman, E. & Potthoff, W. K. Lack of interaction between nitric oxide and the redox modulatory site of the NMDA receptor. Br. J. Pharmacol. 126, 296–300 (1999).
Bredt, D. S. et al. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P–450 reductase. Nature 351, 714–719 (1991).
Kojima, H. et al. Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins. Anal. Chem. 70, 2446–2453 (1998).
Stamler, J. S. & Feelisch, M. in Methods in Nitric Oxide Research (eds. Feelisch, M. & Stamler, J. S.) 521–539 (Wiley, Chichester, 1996).
Brenman, J. E. et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD–95 and α1-syntrophin mediated by PDZ domains. Cell 84, 757–767 (1996).
Lander, H. M. et al. A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J. Biol. Chem. 272, 4323–4326 (1997).
Mannick, J. B. et al. Fas-induced caspase denitrosylation. Science 284, 651–654 (1999).
Monyer, H. et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256, 1217– 1221 (1992).
Sullivan, J. M. et al. Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor. Neuron 13, 929–936 ( 1994).
Choi, Y.-B. & Lipton, S. A. Identification and mechanisms of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor. Neuron 23, 171–180 (1999).
Acknowledgements
We thank J. M. Sullivan and E. Liman for sharing cDNA clones or vectors and T. Lishnak for technical assistance. This work was supported in part by National Institutes of Health grants P01 HD29587, R01 EY05477 and R01 EY09024.
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Choi, YB., Tenneti, L., Le, D. et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat Neurosci 3, 15–21 (2000). https://doi.org/10.1038/71090
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DOI: https://doi.org/10.1038/71090
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