New caged neurotransmitter analogs selective for glutamate receptor sub-types based on methoxynitroindoline and nitrophenylethoxycarbonyl caging groups - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Neuropharmacology Année : 2012

New caged neurotransmitter analogs selective for glutamate receptor sub-types based on methoxynitroindoline and nitrophenylethoxycarbonyl caging groups

Résumé

Photolysis is widely used in experimental neuroscience to isolate post-synaptic receptor activation from presynaptic processes, to determine receptor mechanisms in situ, for pharmacological dissection of signaling pathways, or for photostimulation/inhibition in neural networks.We have evaluated new caged neuroactive amino acids that use 4-methoxy-7-nitroindolinyl- (MNI) or 1-(2-nitrophenyl)ethoxycarbonyl (NPEC) photoprotecting groups to make caged ligands specific for glutamate receptor subtypes. Each was tested for interference with synaptic transmission and excitability and for receptorspecific actions in slice preparations. No adverse effects were found at glutamate receptors. At high concentration, MNI-caged, but not NPEC-caged ligands, interfered with GABA-ergic transmission. MNI-caged amino acids have sub-microsecond release times suitable for investigating mechanisms at fast synaptic receptors in situ. MNI-NMDA and MNI-kainate were synthesized and tested. MNI-NMDA showed stoichiometric release of chirally pure NMDA. Wide-field photolysis in cerebellar interneurons produced a fast-rising sustained activation of NMDA receptors, and localized laser photolysis gave a fast, transient response. Photolysis of MNI-kainate to release up to 4 mMkainate generated large inward currents at resting membrane potential in Purkinje neurons. Application of GYKI 53655 indicated that 40% of the current was due to AMPA receptor activation by kainate. Signaling via metabotropic glutamate receptors (mGluR) does not require fast release rates. NPEC cages are simpler to prepare but have slower photorelease. Photolysis of NPEC-ACPDorNPEC-DHPGinPurkinje neurons generated slowinwardcurrents blockedbythemGluRtype1 antagonist CPCCOEt similar to the slowsEPSC seenwith parallel fiber burst stimulation.NPEC-AMPAwas also tested in Purkinje neurons and showed large sustained inward currents selective for AMPA receptors with little activation of kainate receptors. MNI-caged L-glutamate, NMDA and kainate inhibit GABA-A receptors with IC50 concentrations close to the maximum concentrations useful in receptor signaling experiments.
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hal-03458020 , version 1 (21-11-2022)

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Francisco Palma-Cerda, Céline Auger, Duncan J Crawford, Andrew C.C. Hodgson, Stephen J Reynolds, et al.. New caged neurotransmitter analogs selective for glutamate receptor sub-types based on methoxynitroindoline and nitrophenylethoxycarbonyl caging groups. Neuropharmacology, 2012, 63 (4), pp.624 - 634. ⟨10.1016/j.neuropharm.2012.05.010⟩. ⟨hal-03458020⟩
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