title: Modulation of AMPA receptors by a novel organic nitrate.
abstract: Positive modulators of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) channels reduce desensitization and alter their gating kinetics. We have discovered a novel compound nitric oxide-mimetic that similarly modulates the AMPA receptor by reducing desensitization. This, designated GT-005, belongs to the organic nitrate family that includes the nitrovasodilator nitroglycerine. In acutely isolated hippocampal neurons, GT-005 enhanced kainate (100 microM)-evoked currents with an EC50 of 1.7+/-0.2 mM and a 176+/-10% maximal increase in the steady-state current response. Similar results were found in cultured hippocampal neurons (EC50 of 1.3+/-0.2 mM and a maximal 83+/-14% increase in the steady-state current response). GT-005 reduced the desensitization of glutamate-evoked currents and slowed the onset of desensitization. This compound also increased the rate of recovery from the desensitized state. With respect to alteration of the excitatory synaptic transmission, GT-005 delayed the decay and increased the frequency of spontaneous miniature excitatory postsynaptic currents (mepsc) recorded in cultured hippocampal neurons.
authors.affiliation: Department of Physiology, University of Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Toong
authors.forename: Z G
authors.initials: ZG
authors.lastname: Xiong
authors.forename: S I
authors.initials: SI
authors.lastname: Zavorin
authors.forename: D
authors.initials: D
authors.lastname: Bai
authors.forename: B A
authors.initials: BA
authors.lastname: Orser
authors.forename: G R
authors.initials: GR
authors.lastname: Thatcher
authors.forename: J N
authors.initials: JN
authors.lastname: Reynolds
authors.forename: J F
authors.initials: JF
authors.lastname: MacDonald
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*
chemical_list: C441089:1,2-bis-nitrooxy-3-thiocyanatopropane; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009566:Nitrates; D018091:Receptors, AMPA; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007608:Kainic Acid