Concentration-dependent substate behavior of native AMPA receptors


AMPA-type glutamate receptors mediate most excitatory postsynaptic currents (EPSCs) at central synapses, and their conductance determines in part the size of EPSCs. The conductance of a recombinant AMPA receptor depends on the number of agonist molecules bound to the channel. Here we tested whether native AMPA and kainate receptors show this behavior in outside-out patches from neurons in situ by measuring conductance levels of single channels over a wide range of agonist concentrations. We found that the conductance of AMPA, but not kainate, receptors depended strongly on agonist concentration. Our results suggest that alterations in the glutamate concentration in the synaptic cleft may change the apparent unitary conductance of postsynaptic AMPA receptors.

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Figure 1: Activity of a larger-conductance AMPA receptor over a wide range of agonist concentrations.
Figure 2: Activity of a smaller-conductance AMPA receptor over a wide range of agonist concentrations.
Figure 3: AMPA receptors spend more time in smaller conductance levels in the presence of the competitive antagonist NBQX.
Figure 4: Single-channel activity of a kainate receptor at three concentrations of domoate.
Figure 5: The effect of agonist concentration on the single-channel conductance of native AMPA and kainate receptors.


  1. 1

    Stevens, C. F. Quantal release of neurotransmitter and long-term potentiation. Neuron 10, 55–63 (1993).

    Google Scholar 

  2. 2

    Sigworth, F. J. The variance of sodium current fluctuations at the node of Ranvier. J. Physiol. (Lond.) 307, 97–129 (1980).

    CAS  Article  Google Scholar 

  3. 3

    Traynelis, S. F., Silver, R. A. & Cull-Candy, S. G. Estimated conductance of glutamate receptor channels activated during EPSCs at the cerebellar mossy fiber-granule cell synapse. Neuron 11, 279–289 (1993).

    CAS  Article  Google Scholar 

  4. 4

    Silver, R. A., Cull-Candy, S. G. & Takahashi, T. Non-NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites. J. Physiol. (Lond.) 494, 231–250 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Cull-Candy, S. G., Howe, J. R. & Ogden, D. C. Noise and single channels activated by excitatory amino acids in rat cerebellar granule neurones. J. Physiol. (Lond.) 400, 189–222 (1988).

    CAS  Article  Google Scholar 

  6. 6

    Wyllie, D. J. A., Traynelis, S. F. & Cull-Candy, S. G. Evidence for more than one type of non-NMDA receptor in outside-out patches from cerebellar granule cells of the rat. J. Physiol. (Lond.) 463, 193–226 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Swanson, G. T., Kamboj, S. K. & Cull-Candy, S. G. Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J. Neurosci. 17, 58–69 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Derkach, V., Barria, A. & Soderling, T. R. Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl. Acad. Sci. USA 96, 3269–3274 (1999).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

    Cull-Candy, S. G. & Usowicz, M. M. Multiple-conductance channels activated by excitatory amino acids in cerebellar neurons. Nature 325, 525–528 (1987).

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

    Smith, T. C., Wang, L.-Y. & Howe, J. R. Heterogeneous conductance levels of native AMPA receptors. J. Neurosci. 20, 2073–2085 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Ascher, P., Bregestovski, P. & Nowak, L. N-methyl-D-aspartate-activated channels of mouse central neurones in magnesium-free solutions. J. Physiol. (Lond.) 399, 207–226 (1988).

    CAS  Article  Google Scholar 

  14. 14

    Swanson, G. T., Feldmeyer, D., Kaneda, M. & Cull-Candy, S. G. Effect of editing and subunit co-assembly on single-channel properties of recombinant kainate receptors. J. Physiol. (Lond.) 492, 129–142 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Smith, T. C., Wang, L.-Y. & Howe, J. R. Distinct kainate receptor phenotypes in immature and mature mouse cerebellar granule cells. J. Physiol. (Lond.) 517, 51–58 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Benveniste, M. & Mayer, M. L. Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors: two binding sites each for glutamate and glycine. Biophys. J. 59, 560–573 (1991).

    CAS  Article  Google Scholar 

  17. 17

    Clements, J. D. & Westbrook, G. L. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron 7, 605–613 (1991).

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Google Scholar 

  19. 19

    Herb, A. et al. The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 8, 775–785 (1992).

    CAS  Article  Google Scholar 

  20. 20

    Bahn, S., Volk, B. & Wisden, W. Kainate receptor gene expression in the developing rat brain. J. Neurosci. 14, 5525–5547 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Belcher, S. M. & Howe, J. R. Characterization of RNA editing of the glutamate-receptor subunits GluR5 and GluR6 in granule cells during cerebellar development. Mol. Brain Res. 52, 130–138 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Ripellino, J. A., Neve, R. L. & Howe, J. R. Expression and heteromeric interactions of non-N-methyl-D-aspartate glutamate receptor subunits in the developing and adult cerebellum. Neuroscience 82, 485–497 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Huettner, J. E. Glutamate receptor channels in rat DRG neurons: activation by kainate and quisqualate and blockade of desensitization by Con A. Neuron 5, 255–266 (1990).

    CAS  Article  Google Scholar 

  24. 24

    Partin, K. M., Patneau, D. K., Winters, C. A., Mayer, M. L. & Buonanno, A. Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron 11, 1069–1082 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Howe, J. R. Ion channels formed from the kainate-type subunits GluR6 and KA2 have very small, but different, unitary conductances. J. Neurophysiol. 76, 510–519 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Pemberton, K. E., Belcher, S. M., Ripellino, J. A. & Howe, J. R. High-affininty kainate-type channels in rat cerebellar granule cells. J. Physiol. (Lond.) 510, 401–420 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Traynelis, S. F. & Wahl, P. Control of rat GluR6 glutamate receptor open probability by protein kinase A and calcineurin. J. Physiol. (Lond.) 503, 513–531 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Wilding, T. J. & Huettner, J. E. Activation and desensitization of hippocampal kainate receptors. J. Neurosci. 17, 2713–2721 (1997).

    CAS  Article  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    Clements, J. D. Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci. 19, 163–171 (1996).

    CAS  Article  Google Scholar 

  31. 31

    Diamond, J. D. & Jahr, C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672–4687 (1997).

    CAS  Article  Google Scholar 

  32. 32

    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).

    CAS  Article  Google Scholar 

  33. 33

    Benke, T. A., Lüthi, A., Isaac, J. T. R. & Collingridge, G. L. Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393, 793–797 (1998).

    CAS  Article  Google Scholar 

  34. 34

    Lüscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999).

    Article  Google Scholar 

  35. 35

    Lüthi, A. et al. Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF-GluR2 interaction. Neuron 24, 389–399 (1999).

    Article  Google Scholar 

  36. 36

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Reid, C. A. & Clements, J. D. Postsynaptic expression of long-term potentiation in the rat dentate gyrus demonstrated by variance-mean analysis. J. Physiol. (Lond.) 518, 121–130 (1999).

    CAS  Article  Google Scholar 

  38. 38

    Patlak, J. B. Sodium channel subconductance levels measured with a new variance-mean analysis. J. Gen. Physiol. 92, 413–430 (1988).

    CAS  Article  Google Scholar 

  39. 39

    Sommer, B., Köhler, M., Sprengel, R. & Seeburg, P. H. RNA editing controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11–19 (1991).

    CAS  Article  Google Scholar 

  40. 40

    Donevan, S. D. & Rogawski, M. A. GYKI 52466, a 2,3-benzodiazepine, is a highly selective, non-competitive antagonist of AMPA/kainate receptor responses. Neuron 10, 51–59 (1993).

    CAS  Article  Google Scholar 

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This work was supported by an NIH grant (GM58926) to J.R.H.

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Correspondence to James R. Howe.

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Smith, T., Howe, J. Concentration-dependent substate behavior of native AMPA receptors. Nat Neurosci 3, 992–997 (2000).

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