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Titolo:
Mechanism and impact of allosteric AMPA receptor modulation by the Ampakine (TM) CX546
Autore:
Nagarajan, N; Quast, C; Boxall, AR; Shahid, M; Rosenmund, C;
Indirizzi:
Max Planck Inst Biophys Chem, Dept Membrane Biophys, D-37070 Gottingen, Germany Max Planck Inst Biophys Chem Gottingen Germany D-37070 ottingen, Germany Organon Res Labs Ltd, Dept Pharmacol, Newhouse ML1 5SH, Lanark, Scotland Organon Res Labs Ltd Newhouse Lanark Scotland ML1 5SH H, Lanark, Scotland
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 6, volume: 41, anno: 2001,
pagine: 650 - 663
SICI:
0028-3908(200111)41:6<650:MAIOAA>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT HIPPOCAMPAL-NEURONS; LIGAND-BINDING CORE; GLUTAMATE RECEPTORS; 7-CHLORO-3-METHYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE S,S-DIOXIDE; SYNAPTIC TRANSMISSION; ACTIVATION KINETICS; KAINATE RECEPTORS; TIME-COURSE; DESENSITIZATION; CYCLOTHIAZIDE;
Keywords:
desensitization; allosteric mechanism; hippocampus; benzothiadiazides; benzoylpiperidines; synaptic transmission;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
58
Recensione:
Indirizzi per estratti:
Indirizzo: Rosenmund, C Max Planck Inst Biophys Chem, Dept Membrane Biophys, D-37070 Gottingen, Germany Max Planck Inst Biophys Chem Gottingen Germany D-37070many
Citazione:
N. Nagarajan et al., "Mechanism and impact of allosteric AMPA receptor modulation by the Ampakine (TM) CX546", NEUROPHARM, 41(6), 2001, pp. 650-663

Abstract

Glutamate release at central synapses is transduced into a characteristic fast postsynaptic response by AMPA receptor gating and agonist affinity. The effect of two classes of modulators of AMPA receptor desensitization. thebenzothiadiazides (cyclothiazide and IDRA 21) and the benzoylpiperidines (CX516 and CX546), were studied on gating kinetics of recombinant, native AMPA receptors and on synaptic currents. CX546 reduced the degree of desensitization more potently than CX516 or IDRA 21, but not as efficiently as cyclothiazide. In presence of CX516/CX546, desensitization of GluR2(fhp) receptors was inhibited more than of GluR1(fhp), whereas they had no effect upon response shape or conductance. CX546 increased agonist affinity threefold on nondesensitizing AMPA receptors by slowing agonist unbinding. Analysis ofmodulatory action suggests that, in contrast to cyclothiazide or IDRA 21, the Ampakine (TM) CX546 binds specifically to the agonist bound nondesensitized receptor. most likely acting by destabilizing the desensitized receptor conformation. All modulators tested showed higher efficiency on native receptors as compared to homomeric receptors. At the glutamatergic synapse, evoked synaptic amplitudes were weakly potentiated, while EPSC decay was slowed by nearly a factor of three in the presence of CX546 or cyclothiazide. In the presence of CX546, the current induced by short pulses of glutamate from recombinant GluR2 receptors decayed with a time course that was approximately twentyfold faster than EPSCs. The unique properties of CX546 may bebeneficial for therapeutical use. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/07/20 alle ore 07:22:08