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Modal gating of NMDA receptors and the shape of their synaptic response

Abstract

N-methyl-D-aspartate receptor (NMDAR) channels mediate the slow component of excitatory potentials at glutamatergic synapses. They have complex kinetic behavior, and much remains to be understood about NMDAR gating mechanisms and the molecular events that shape the synaptic current. Here we show that an individual NMDAR produces at least three stable patterns of activity. For all modes, channels gate by the same mechanism and can occupy either of two open states. The relative stability of the open states differs across modes because of a common perturbation to the NMDAR structure that may be subject to cellular control. Simulations indicate that native NMDAR-mediated synaptic responses arise mainly from the most common mode, and that the slow rise and decay of the current can be attributed to multiple transitions between fully liganded open and closed states rather than to agonist dissociation.

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Figure 1: Single-channel currents elicited by saturating concentrations of agonists without EDTA.
Figure 2: Modal gating of single-channel currents elicited by saturating concentrations of agonists in the presence of EDTA.
Figure 3: Modal gating of NMDAR in four example patches.
Figure 4: Modeling modes.
Figure 5: Energy landscapes of NMDAR gating.
Figure 6: Simulations of the NMDAR synaptic response to a 1-ms pulse of transmitter.

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References

  1. Attwell, D. & Laughlin, S.B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).

    Article  CAS  Google Scholar 

  2. McBain, C.J. & Mayer, M.L. N-methyl-D-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–760 (1994).

    Article  CAS  Google Scholar 

  3. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

    CAS  PubMed  Google Scholar 

  4. Rosenmund, C., Stern-Bach, Y. & Stevens, C.F. The tetrameric structure of a glutamate receptor channel [see comments]. Science 280, 1596–1599 (1998).

    Article  CAS  Google Scholar 

  5. Behe, P. et al. Determination of NMDA NR1 subunit copy number in recombinant NMDA receptors. Proc. R. Soc. Lond. B Biol. Sci. 262, 205–213 (1995).

    Article  CAS  Google Scholar 

  6. Premkumar, L.S. & Auerbach, A. Stoichiometry of recombinant N-methyl-D-aspartate receptor channels inferred from single-channel current patterns. J. Gen. Physiol. 110, 485–502 (1997).

    Article  CAS  Google Scholar 

  7. Lester, R.A. & Jahr, C.E. NMDA channel behavior depends on agonist affinity. J. Neurosci. 12, 635–643 (1992).

    Article  CAS  Google Scholar 

  8. Jahr, C.E. & Stevens, C.F. A quantitative description of NMDA receptor-channel kinetic behavior. J. Neurosci. 10, 1830–1837 (1990).

    Article  CAS  Google Scholar 

  9. Howe, J.R., Cull-Candy, S.G. & Colquhoun, D. Currents through single glutamate receptor channels in outside-out patches from rat cerebellar granule cells. J. Physiol. (Lond.) 432, 143–202 (1991).

    Article  CAS  Google Scholar 

  10. Gibb, A.J. & Colquhoun, D. Glutamate activation of a single NMDA receptor-channel produces a cluster of channel openings. Proc. R. Soc. Lond. B Biol. Sci. 243, 39–45 (1991).

    Article  CAS  Google Scholar 

  11. Kleckner, N.W. & Pallotta, B.S. Burst kinetics of single NMDA receptor currents in cell-attached patches from rat brain cortical neurons in culture. J. Physiol. 486, 411–426 (1995).

    Article  CAS  Google Scholar 

  12. Stern, P., Cik, M., Colquhoun, D. & Stephenson, F.A. Single channel properties of cloned NMDA receptors in a human cell line: comparison with results from Xenopus oocytes. J. Physiol. (Lond.) 476, 391–397 (1994).

    Article  CAS  Google Scholar 

  13. Wyllie, D.J., Behe, P. & Colquhoun, D. Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors. J. Physiol. 510, 1–18 (1998).

    Article  CAS  Google Scholar 

  14. Sakmann, B., Patlak, J. & Neher, E. Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist. Nature 286, 71–73 (1980).

    Article  CAS  Google Scholar 

  15. Premkumar, L.S. & Auerbach, A. Identification of a high affinity divalent cation binding site near the entrance of the NMDA receptor channel. Neuron 16, 869–880 (1996).

    Article  CAS  Google Scholar 

  16. Zhu, Y. & Auerbach, A. Na+ occupancy and Mg2+ block of the N-methyl-D-aspartate receptor channel. J. Gen. Physiol. 117, 275–286 (2001).

    Article  CAS  Google Scholar 

  17. Vissel, B., Krupp, J.J., Heinemann, S.F. & Westbrook, G.L. A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux. Nat. Neurosci. 4, 587–596 (2001).

    Article  CAS  Google Scholar 

  18. Leffler, J.E. & Grunwald, E. Rates and Equilibria of Organic Reactions (Wiley, New York, 1963).

    Google Scholar 

  19. Jahr, C.E. High probability opening of NMDA receptor channels by L-glutamate. Science 255, 470–472 (1992).

    Article  CAS  Google Scholar 

  20. Forsythe, I.D. & Westbrook, G.L. Slow excitatory postsynaptic currents mediated by N-methyl-D-aspartate receptors on cultured mouse central neurones. J. Physiol. 396, 515–533 (1988).

    Article  CAS  Google Scholar 

  21. Hestrin, S., Sah, P. & Nicoll, R.A. Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices. Neuron 5, 247–253 (1990).

    Article  CAS  Google Scholar 

  22. Lester, R.A., Clements, J.D., Westbrook, G.L. & Jahr, C.E. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346, 565–567 (1990).

    Article  CAS  Google Scholar 

  23. Vicini, S. et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J. Neurophysiol. 79, 555–566 (1998).

    Article  CAS  Google Scholar 

  24. Jahr, C.E. & Stevens, C.F. Glutamate activates multiple single channel conductances in hippocampal neurons. Nature 325, 522–525 (1987).

    Article  CAS  Google Scholar 

  25. Howe, J.R., Colquhoun, D. & Cull-Candy, S.G. On the kinetics of large-conductance glutamate-receptor ion channels in rat cerebellar granule neurons. Proc. R. Soc. Lond. B Biol. Sci. 233, 407–422 (1988).

    Article  CAS  Google Scholar 

  26. Auerbach, A. & Lingle, C.J. Heterogeneous kinetic properties of acetylcholine receptor channels in Xenopus myocytes. J. Physiol. 378, 119–140 (1986).

    Article  CAS  Google Scholar 

  27. Naranjo, D. & Brehm, P. Modal shifts in acetylcholine receptor channel gating confer subunit-dependent desensitization. Science 260, 1811–1814 (1993).

    Article  CAS  Google Scholar 

  28. Milone, M. et al. Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. Neuron 20, 575–588 (1998).

    Article  CAS  Google Scholar 

  29. Howe, J.R. & Ritchie, J.M. Multiple kinetic components of sodium channel inactivation in rabbit Schwann cells. J. Physiol. 455, 529–566 (1992).

    Article  CAS  Google Scholar 

  30. Yakubovich, D., Pastushenko, V., Bitler, A., Dessauer, C.W. & Dascal, N. Slow modal gating of single G protein-activated K+ channels expressed in Xenopus oocytes. J. Physiol. 524, 737–755 (2000).

    Article  CAS  Google Scholar 

  31. Ivanova-Nikolova, T.T., Nikolov, E.N., Hansen, C. & Robishaw, J.D. Muscarinic K+ channel in the heart. Modal regulation by G protein beta gamma subunits. J. Gen. Physiol. 112, 199–210 (1998).

    Article  CAS  Google Scholar 

  32. Dreyer, I., Michard, E., Lacombe, B. & Thibaud, J.B. A plant Shaker-like K+ channel switches between two distinct gating modes resulting in either inward-rectifying or “leak” current. FEBS Lett. 505, 233–239 (2001).

    Article  CAS  Google Scholar 

  33. Delcour, A.H., Lipscombe, D. & Tsien, R.W. Multiple modes of N-type calcium channel activity distinguished by differences in gating kinetics. J. Neurosci. 13, 181–194 (1993).

    Article  CAS  Google Scholar 

  34. Delcour, A.H. & Tsien, R.W. Altered prevalence of gating modes in neurotransmitter inhibition of N- type calcium channels. Science 259, 980–984 (1993).

    Article  CAS  Google Scholar 

  35. Catacuzzeno, L., Trequattrini, C., Petris, A. & Franciolini, F. Bimodal kinetics of a chloride channel from human fibroblasts. J. Membr. Biol. 170, 165–172 (1999).

    Article  CAS  Google Scholar 

  36. Banke, T.G. & Traynelis, S.F. Activation of NR1/NR2B NMDA receptors. Nat. Neurosci. 6, 144–152 (2003).

    Article  CAS  Google Scholar 

  37. Grosman, C. & Auerbach, A. The dissociation of acetylcholine from open nicotinic receptor channels. Proc. Natl. Acad. Sci. USA 98, 14102–14107 (2001).

    Article  CAS  Google Scholar 

  38. Moriyoshi, K. et al. Molecular cloning and characterization of the rat NMDA receptor [see comments]. Nature 354, 31–37 (1991).

    Article  CAS  Google Scholar 

  39. Monyer, H. et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256, 1217–1221 (1992).

    Article  CAS  Google Scholar 

  40. Chen, C. & Okayama, H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7, 2745–2752 (1987).

    Article  CAS  Google Scholar 

  41. Hamill, O.P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F.J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 391, 85–100 (1981).

    Article  CAS  Google Scholar 

  42. Qin, F., Auerbach, A. & Sachs, F. Maximum likelihood estimation of aggregated Markov processes. Proc. R. Soc. Lond. B Biol. Sci. 264, 375–383 (1997).

    Article  CAS  Google Scholar 

  43. Magleby, K.L. & Pallotta, B.S. Burst kinetics of single calcium-activated potassium channels in cultured rat muscle. J. Physiol. 344, 605–623 (1983).

    Article  CAS  Google Scholar 

  44. Clements, J.D., Lester, R.A., Tong, G., Jahr, C.E. & Westbrook, G.L. The time course of glutamate in the synaptic cleft. Science 258, 1498–1501 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Bailey and M. Teeling for technical assistance, C. Nicolai for computer programming, P. Seeburg and T. Kuner for the NMDAR subunit cDNAs and G. Westbrook for the NR1838STOP cDNA. This work was supported by NIH (NS036554 to A.A. and DA015164 to G.P.).

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Correspondence to Gabriela Popescu or Anthony Auerbach.

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Popescu, G., Auerbach, A. Modal gating of NMDA receptors and the shape of their synaptic response. Nat Neurosci 6, 476–483 (2003). https://doi.org/10.1038/nn1044

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