title: Ligand-dependent opening of the multiple AMPA receptor conductance states: a concerted model.
abstract: Modulation of the properties of AMPA receptors at the post-synaptic membrane is one of the main suggested mechanisms underlying fast synaptic transmission in the central nervous system of vertebrates. Electrophysiological recordings of single channels stimulated with agonists showed that both recombinant and native AMPA receptors visit multiple conductance states in an agonist concentration dependent manner. We propose an allosteric model of the multiple conductance states based on concerted conformational transitions of the four subunits, as an iris diaphragm. Our model predicts that the thermodynamic behaviour of the conductance states upon full and partial agonist stimulations can be described with increased affinity of receptors as they progress to higher conductance states. The model also predicts the existence of AMPA receptors in non-liganded conductive substates. However, the probability of spontaneous openings decreases with increasing conductances. Finally, we predict that the large conductance states are stabilized within the rise phase of a whole-cell EPSC in glutamatergic hippocampal neurons. Our model provides a mechanistic link between ligand concentration and conductance states that can explain thermodynamic and kinetic features of AMPA receptor gating.
authors: Department of Medicine Solna, Karolinska Insitutet, 171 76 Stockholm, Sweden; NWFZ, Charite Universitatsmedizin, 101 17 Berlin, Germany; European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
authors: Ranjita
authors: R
authors: Dutta-Roy
authors: NWFZ, Charite Universitatsmedizin, 101 17 Berlin, Germany.
authors: Christian
authors: C
authors: Rosenmund
authors: The Babraham Institute, Babraham, Cambridgeshire CB22 3AT, UK.
authors: Stuart J
authors: SJ
authors: Edelstein
authors: European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK; The Babraham Institute, Babraham, Cambridgeshire CB22 3AT, UK.
authors: Nicolas
authors: N
authors: Le Novère
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008959:Models, Neurological; D011485:Protein Binding; D017966:Pyramidal Cells / Q000378:metabolism; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D008024:Ligands; D018091:Receptors, AMPA
references: Nat Rev Neurosci. 2007 Aug;8(8):597-609
references: 17637801
references: Curr Opin Neurobiol. 2007 Jun;17(3):281-8
references: 17419047
references: Nature. 2009 Dec 10;462(7274):745-56
references: 19946266
references: Neurosci Res. 2010 Jan;66(1):92-8
references: 19818370
references: Pharmacol Rev. 2010 Sep;62(3):405-96
references: 20716669
references: Nat Chem Biol. 2011 Mar;7(3):168-73
references: 21297640
references: BMC Syst Biol. 2011;5:198
references: 22172142
references: Science. 2012 Aug 10;337(6095):749-53
references: 22767895
references: PLoS One. 2012;7(9):e44388
references: 23049748
references: Neuron. 2013 Aug 7;79(3):492-503
references: 23931998
references: Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E3987-96
references: 24043807
references: J Neurosci. 2000 Mar 15;20(6):2073-85
references: 10704481
references: Nat Neurosci. 2000 Oct;3(10):992-7
references: 11017171
references: Neuron. 2000 Oct;28(1):165-81
references: 11086992
references: J Gen Physiol. 2002 Sep;120(3):267-305
references: 12198087
references: Bioinformatics. 2003 Mar 1;19(4):524-31
references: 12611808
references: Nat Neurosci. 2003 Aug;6(8):803-10
references: 12872125
references: J Physiol. 2004 Jan 15;554(Pt 2):249-53
references: 14645452
references: Neuron. 2004 Feb 5;41(3):309-11
references: 14766169
references: J Neurophysiol. 2004 Oct;92(4):2456-67
references: 15115789
references: Biochemistry. 1966 Jan;5(1):365-85
references: 5938952
references: Proc Natl Acad Sci U S A. 1984 Jun;81(12):3901-4
references: 6328531
references: Nature. 1987 Feb 5-11;325(6104):525-8
references: 2433594
references: Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7834-8
references: 1679238
references: Science. 1992 Nov 27;258(5087):1498-501
references: 1359647
references: J Physiol. 1993 Dec;472:615-63
references: 7908327
references: Neuron. 1994 Dec;13(6):1345-57
references: 7527641
references: Biol Cybern. 1996 Nov;75(5):361-79
references: 8983160
references: J Neurosci. 1997 Jun 15;17(12):4672-87
references: 9169528
references: Biochemistry. 1997 Nov 11;36(45):13755-60
references: 9374851
references: Eur J Neurosci. 1997 Oct;9(10):1999-2008
references: 9421161
references: Science. 1998 Jun 5;280(5369):1596-9
references: 9616121
references: Neuron. 1998 Nov;21(5):959-80
references: 9856454
references: J Gen Physiol. 1999 Jun;113(6):873-95
references: 10352036
references: J Biol Chem. 1999 Jul 9;274(28):19623-9
references: 10391899
references: J Mol Biol. 1965 May;12:88-118
references: 14343300
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D689-91
references: 16381960
references: J Physiol. 2006 Jun 1;573(Pt 2):371-94
references: 16527860
references: Bioinformatics. 2006 Dec 15;22(24):3067-74
references: 17032683
references: Nature. 2009 Jan 1;457(7225):111-4
references: 18987633