Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structural mechanisms of activation and desensitization in neurotransmitter-gated ion channels

Nature Structural & Molecular Biology volume 23, pages 494–502 (2016)Cite this article

Subjects

Numerous recent crystal and cryo-EM structures have greatly advanced understanding of the functional mechanisms of neurotransmitter-gated ion channels. This Review discusses the structural basis of activation and desensitization mechanisms in glutamate and cysteine-loop receptors.

Abstract

Ion channels gated by neurotransmitters are present across metazoans, in which they are essential for brain function, sensation and locomotion; closely related homologs are also found in bacteria. Structures of eukaryotic pentameric cysteine-loop (Cys-loop) receptors and tetrameric ionotropic glutamate receptors in multiple functional states have recently become available. Here, I describe how these studies relate to established ideas regarding receptor activation and how they have enabled decades' worth of functional work to be pieced together, thus allowing previously puzzling aspects of receptor activity to be understood.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Architecture and neurotransmitter binding in GluRs.
Figure 2: Architecture and ligand binding in CLRs.
Figure 3: Gating and desensitization of CLRs.
Figure 4: Gating and desensitization in GluRs.
Figure 5: Interfaces in CLRs and GluRs.

Accession codes

Accessions

Protein Data Bank

References

  1. Langley, J.N. On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. J. Physiol. (Lond.) 33, 374–413 (1905).

    Article  Google Scholar 

  2. Neher, E. & Sakmann, B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature 260, 799–802 (1976).

    Article  CAS  PubMed  Google Scholar 

  3. Miyazawa, A., Fujiyoshi, Y. & Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423, 949–955 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Benton, R., Vannice, K.S., Gomez-Diaz, C. & Vosshall, L.B. Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila . Cell 136, 149–162 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kawate, T., Michel, J.C., Birdsong, W.T. & Gouaux, E. Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature 460, 592–598 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jasti, J., Furukawa, H., Gonzales, E.B. & Gouaux, E. Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature 449, 316–323 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Li, M., Toombes, G.E., Silberberg, S.D. & Swartz, K.J. Physical basis of apparent pore dilation of ATP-activated P2X receptor channels. Nat. Neurosci. 18, 1577–1583 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Stern-Bach, Y. et al. Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins. Neuron 13, 1345–1357 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Uchino, S., Sakimura, K., Nagahari, K. & Mishina, M. Mutations in a putative agonist binding region of the AMPA-selective glutamate receptor channel. FEBS Lett. 308, 253–257 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Abele, R., Keinanen, K. & Madden, D.R. Agonist-induced isomerization in a glutamate receptor ligand-binding domain: a kinetic and mutagenetic analysis. J. Biol. Chem. 275, 21355–21363 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Cheng, Q., Du, M., Ramanoudjame, G. & Jayaraman, V. Evolution of glutamate interactions during binding to a glutamate receptor. Nat. Chem. Biol. 1, 329–332 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Jin, R., Banke, T.G., Mayer, M.L., Traynelis, S.F. & Gouaux, E. Structural basis for partial agonist action at ionotropic glutamate receptors. Nat. Neurosci. 6, 803–810 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Inanobe, A., Furukawa, H. & Gouaux, E. Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron 47, 71–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Lau, A.Y. & Roux, B. The hidden energetics of ligand binding and activation in a glutamate receptor. Nat. Struct. Mol. Biol. 18, 283–287 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ahmed, A.H., Wang, S., Chuang, H.H. & Oswald, R.E. Mechanism of AMPA receptor activation by partial agonists: disulfide trapping of closed lobe conformations. J. Biol. Chem. 286, 35257–35266 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Robert, A., Armstrong, N., Gouaux, J.E. & Howe, J.R. AMPA receptor binding cleft mutations that alter affinity, efficacy, and recovery from desensitization. J. Neurosci. 25, 3752–3762 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jin, R., Horning, M., Mayer, M.L. & Gouaux, E. Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate. Biochemistry 41, 15635–15643 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Furukawa, H. & Gouaux, E. Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core. EMBO J. 22, 2873–2885 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Alberstein, R., Grey, R., Zimmet, A., Simmons, D.K. & Mayer, M.L. Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes. Proc. Natl. Acad. Sci. USA 112, E6048–E6057 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. MacGillavry, H.D., Song, Y., Raghavachari, S. & Blanpied, T.A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Raghavachari, S. & Lisman, J.E. Properties of quantal transmission at CA1 synapses. J. Neurophysiol. 92, 2456–2467 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 3, 102–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Zhong, W. et al. From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor. Proc. Natl. Acad. Sci. USA 95, 12088–12093 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Brejc, K. et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Spurny, R. et al. Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. USA 112, E2543–E2552 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Li, S.X. et al. Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist. Nat. Neurosci. 14, 1253–1259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Miller, P.S. & Aricescu, A.R. Crystal structure of a human GABAA receptor. Nature 512, 270–275 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hassaine, G. et al. X-ray structure of the mouse serotonin 5-HT3 receptor. Nature 512, 276–281 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Du, J., Lü, W., Wu, S., Cheng, Y. & Gouaux, E. Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature 526, 224–229 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang, X., Chen, H., Michelsen, K., Schneider, S. & Shaffer, P.L. Crystal structure of human glycine receptor-α3 bound to antagonist strychnine. Nature 526, 277–280 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Meyerson, J.R. et al. Structural mechanism of glutamate receptor activation and desensitization. Nature 514, 328–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lau, A.Y. et al. A conformational intermediate in glutamate receptor activation. Neuron 79, 492–503 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Baranovic, J. et al. Dynamics of the ligand binding domain layer during AMPA receptor activation. Biophys. J. 110, 896–911 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sobolevsky, A.I., Rosconi, M.P. & Gouaux, E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462, 745–756 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kazi, R., Dai, J., Sweeney, C., Zhou, H.X. & Wollmuth, L.P. Mechanical coupling maintains the fidelity of NMDA receptor–mediated currents. Nat. Neurosci. 17, 914–922 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Balannik, V., Menniti, F.S., Paternain, A.V., Lerma, J. & Stern-Bach, Y. Molecular mechanism of AMPA receptor noncompetitive antagonism. Neuron 48, 279–288 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Watanabe, J., Beck, C., Kuner, T., Premkumar, L.S. & Wollmuth, L.P. DRPEER: a motif in the extracellular vestibule conferring high Ca2+ flux rates in NMDA receptor channels. J. Neurosci. 22, 10209–10216 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Talukder, I., Borker, P. & Wollmuth, L.P. Specific sites within the ligand-binding domain and ion channel linkers modulate NMDA receptor gating. J. Neurosci. 30, 11792–11804 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schmid, S.M., Körber, C., Herrmann, S., Werner, M. & Hollmann, M. A domain linking the AMPA receptor agonist binding site to the ion pore controls gating and causes lurcher properties when mutated. J. Neurosci. 27, 12230–12241 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bourne, Y., Talley, T.T., Hansen, S.B., Taylor, P. & Marchot, P. Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J. 24, 1512–1522 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mukhtasimova, N., Lee, W.Y., Wang, H.L. & Sine, S.M. Detection and trapping of intermediate states priming nicotinic receptor channel opening. Nature 459, 451–454 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Purohit, P. & Auerbach, A. Loop C and the mechanism of acetylcholine receptor-channel gating. J. Gen. Physiol. 141, 467–478 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pan, J. et al. Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine. Nat. Commun. 3, 714 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rajendra, S. et al. Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor. J. Biol. Chem. 269, 18739–18742 (1994).

    CAS  PubMed  Google Scholar 

  46. Lee, W.Y. & Sine, S.M. Principal pathway coupling agonist binding to channel gating in nicotinic receptors. Nature 438, 243–247 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Lape, R., Plested, A.J., Moroni, M., Colquhoun, D. & Sivilotti, L.G. The α1K276E startle disease mutation reveals multiple intermediate states in the gating of glycine receptors. J. Neurosci. 32, 1336–1352 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. daCosta, C.J., Free, C.R. & Sine, S.M. Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors. Nat. Commun. 6, 8057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Purohit, P., Bruhova, I., Gupta, S. & Auerbach, A. Catch-and-hold activation of muscle acetylcholine receptors having transmitter binding site mutations. Biophys. J. 107, 88–99 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lape, R., Colquhoun, D. & Sivilotti, L.G. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454, 722–727 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Burzomato, V., Beato, M., Groot-Kormelink, P.J., Colquhoun, D. & Sivilotti, L.G. Single-channel behavior of heteromeric alpha1beta glycine receptors: an attempt to detect a conformational change before the channel opens. J. Neurosci. 24, 10924–10940 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kussius, C.L. & Popescu, G.K. Kinetic basis of partial agonism at NMDA receptors. Nat. Neurosci. 12, 1114–1120 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schorge, S., Elenes, S. & Colquhoun, D. Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits. J. Physiol. (Lond.) 569, 395–418 (2005).

    Article  CAS  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. Auerbach, A. Dose-response analysis when there is a correlation between affinity and efficacy. Mol. Pharmacol. 89, 297–302 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Unwin, N. Acetylcholine receptor channel imaged in the open state. Nature 373, 37–43 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Hilf, R.J. & Dutzler, R. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457, 115–118 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Bocquet, N. et al. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457, 111–114 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Hilf, R.J. & Dutzler, R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452, 375–379 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Sauguet, L. et al. Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation. Proc. Natl. Acad. Sci. USA 111, 966–971 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Gonzalez-Gutierrez, G. & Grosman, C. The atypical cation-conduction and gating properties of ELIC underscore the marked functional versatility of the pentameric ligand-gated ion-channel fold. J. Gen. Physiol. 146, 15–36 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dellisanti, C.D. et al. Site-directed spin labeling reveals pentameric ligand-gated ion channel gating motions. PLoS Biol. 11, e1001714 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hibbs, R.E. & Gouaux, E. Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474, 54–60 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Althoff, T., Hibbs, R.E., Banerjee, S. & Gouaux, E. X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512, 333–337 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Purohit, P., Gupta, S., Jadey, S. & Auerbach, A. Functional anatomy of an allosteric protein. Nat. Commun. 4, 2984 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Grosman, C., Zhou, M. & Auerbach, A. Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403, 773–776 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Cymes, G.D., Ni, Y. & Grosman, C. Probing ion-channel pores one proton at a time. Nature 438, 975–980 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Beato, M., Groot-Kormelink, P.J., Colquhoun, D. & Sivilotti, L.G. The activation mechanism of alpha1 homomeric glycine receptors. J. Neurosci. 24, 895–906 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rayes, D., De Rosa, M.J., Sine, S.M. & Bouzat, C. Number and locations of agonist binding sites required to activate homomeric Cys-loop receptors. J. Neurosci. 29, 6022–6032 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Doyle, D.A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Alam, A. & Jiang, Y. High-resolution structure of the open NaK channel. Nat. Struct. Mol. Biol. 16, 30–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Dürr, K.L. et al. Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell 158, 778–792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen, L., Dürr, K.L. & Gouaux, E. X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism. Science 345, 1021–1026 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yelshanskaya, M.V., Li, M. & Sobolevsky, A.I. Structure of an agonist-bound ionotropic glutamate receptor. Science 345, 1070–1074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sobolevsky, A.I., Yelshansky, M.V. & Wollmuth, L.P. The outer pore of the glutamate receptor channel has 2-fold rotational symmetry. Neuron 41, 367–378 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Lee, C.-H. et al. NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511, 191–197 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Karakas, E. & Furukawa, H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science 344, 992–997 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Weston, M.C., Schuck, P., Ghosal, A., Rosenmund, C. & Mayer, M.L. Conformational restriction blocks glutamate receptor desensitization. Nat. Struct. Mol. Biol. 13, 1120–1127 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Carbone, A.L. & Plested, A.J. Coupled control of desensitization and gating by the ligand binding domain of glutamate receptors. Neuron 74, 845–857 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Klein, R.M. & Howe, J.R. Effects of the lurcher mutation on GluR1 desensitization and activation kinetics. J. Neurosci. 24, 4941–4951 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yelshansky, M.V., Sobolevsky, A.I., Jatzke, C. & Wollmuth, L.P. Block of AMPA receptor desensitization by a point mutation outside the ligand-binding domain. J. Neurosci. 24, 4728–4736 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yelshanskaya, M.V., Saotome, K., Singh, A.K. & Sobolevsky, A.I. Probing intersubunit interfaces in AMPA-subtype ionotropic glutamate receptors. Sci. Rep. 6, 19082 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Das, U., Kumar, J., Mayer, M.L. & Plested, A.J. Domain organization and function in GluK2 subtype kainate receptors. Proc. Natl. Acad. Sci. USA 107, 8463–8468 (2010).

    Article  PubMed  Google Scholar 

  84. Gielen, M., Siegler Retchless, B., Mony, L., Johnson, J.W. & Paoletti, P. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459, 703–707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wilding, T.J., Lopez, M.N. & Huettner, J.E. Radial symmetry in a chimeric glutamate receptor pore. Nat. Commun. 5, 3349 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Auerbach, A. & Akk, G. Desensitization of mouse nicotinic acetylcholine receptor channels. A two-gate mechanism. J. Gen. Physiol. 112, 181–197 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Colquhoun, D. & Sakmann, B. Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. J. Physiol. (Lond.) 369, 501–557 (1985).

    Article  CAS  PubMed Central  Google Scholar 

  88. daCosta, C.J., Free, C.R., Corradi, J., Bouzat, C. & Sine, S.M. Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation. J. Neurosci. 31, 13870–13879 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hosie, A.M., Wilkins, M.E., da Silva, H.M. & Smart, T.G. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444, 486–489 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Gielen, M., Thomas, P. & Smart, T.G. The desensitization gate of inhibitory Cys-loop receptors. Nat. Commun. 6, 6829 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gill, S.B., Veruki, M.L. & Hartveit, E. Functional properties of spontaneous IPSCs and glycine receptors in rod amacrine (AII) cells in the rat retina. J. Physiol. (Lond.) 575, 739–759 (2006).

    Article  CAS  Google Scholar 

  92. Jones, M.V. & Westbrook, G.L. Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15, 181–191 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Zhu, W.J. & Vicini, S. Neurosteroid prolongs GABAA channel deactivation by altering kinetics of desensitized states. J. Neurosci. 17, 4022–4031 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Franke, C., Hatt, H., Parnas, H. & Dudel, J. Recovery from the rapid desensitization of nicotinic acetylcholine receptor channels on mouse muscle. Neurosci. Lett. 140, 169–172 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Elenes, S. & Auerbach, A. Desensitization of diliganded mouse muscle nicotinic acetylcholine receptor channels. J. Physiol. (Lond.) 541, 367–383 (2002).

    Article  CAS  Google Scholar 

  96. Tovar, K.R. & Westbrook, G.L. Amino-terminal ligands prolong NMDA receptor-mediated EPSCs. J. Neurosci. 32, 8065–8073 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Karakas, E., Simorowski, N. & Furukawa, H. Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature 475, 249–253 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Teissére, J.A. & Czajkowski, C. A β-strand in the γ2 subunit lines the benzodiazepine binding site of the GABA A receptor: structural rearrangements detected during channel gating. J. Neurosci. 21, 4977–4986 (2001).

    Article  PubMed  Google Scholar 

  99. Lynch, G. Glutamate-based therapeutic approaches: ampakines. Curr. Opin. Pharmacol. 6, 82–88 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Sun, Y. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Franks, N.P. & Lieb, W.R. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science 254, 427–430 (1991).

    Article  CAS  PubMed  Google Scholar 

  102. Mihic, S.J. et al. Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 389, 385–389 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Yip, G.M. et al. A propofol binding site on mammalian GABAA receptors identified by photolabeling. Nat. Chem. Biol. 9, 715–720 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Li, G.D. et al. Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J. Neurosci. 26, 11599–11605 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nury, H. et al. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469, 428–431 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Sanna, E., Garau, F. & Harris, R.A. Novel properties of homomeric beta 1 gamma-aminobutyric acid type A receptors: actions of the anesthetics propofol and pentobarbital. Mol. Pharmacol. 47, 213–217 (1995).

    CAS  PubMed  Google Scholar 

  107. Liebeskind, B.J., Hillis, D.M. & Zakon, H.H. Convergence of ion channel genome content in early animal evolution. Proc. Natl. Acad. Sci. USA 112, E846–E851 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Gielen, M.C., Lumb, M.J. & Smart, T.G. Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding. J. Neurosci. 32, 5707–5715 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Plested, A.J.R., Vijayan, R., Biggin, P.C. & Mayer, M.L. Molecular basis of kainate receptor modulation by sodium. Neuron 58, 720–735 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dawe, G.B. et al. Defining the structural relationship between kainate-receptor deactivation and desensitization. Nat. Struct. Mol. Biol. 20, 1054–1061 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Herguedas, B. et al. Structure and organization of heteromeric AMPA-type glutamate receptors. Science http://dx.doi.org/10.1126/science.aad3873 (2016).

  112. Tomita, S. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Carbone, A.L. & Plested, A.J. Superactivation of AMPA receptors by auxiliary proteins. Nat. Commun. 7, 10178 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Miwa, J.M. et al. lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron 23, 105–114 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Nichols, W.A. et al. Lynx1 shifts α4β2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum. J. Biol. Chem. 289, 31423–31432 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, W., Howe, J.R. & Popescu, G.K. Distinct gating modes determine the biphasic relaxation of NMDA receptor currents. Nat. Neurosci. 11, 1373–1375 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang, W., Devi, S.P., Tomita, S. & Howe, J.R. Auxiliary proteins promote modal gating of AMPA- and kainate-type glutamate receptors. Eur. J. Neurosci. 39, 1138–1147 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Doudna, J.A. & Charpentier, E. Genome editing: the new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Pettersen, E.F. et al. UCSF Chimera: a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article  CAS  Google Scholar 

  120. Spurny, R. et al. Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines. Proc. Natl. Acad. Sci. USA 109, E3028–E3034 (2012).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

I thank J. Baranovic, M. Poulsen, C. Eibl, C. Czajkowski and C. Grosman for comments on the manuscript. Figures were prepared with PyMOL (http://www.pymol.org/) and the UCSF Chimera package119. Chimera was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).

Author information

Authors and Affiliations

  1. Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany

    Andrew J R Plested

  2. NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Andrew J R Plested

Authors
  1. Andrew J R Plested
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew J R Plested.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Plested, A. Structural mechanisms of activation and desensitization in neurotransmitter-gated ion channels. Nat Struct Mol Biol 23, 494–502 (2016). https://doi.org/10.1038/nsmb.3214

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3214

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing