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Titolo:
INTERACTIONS OF GYKI-52466 AND NBQX WITH CYCLOTHIAZIDE AT AMPA RECEPTORS - EXPERIMENTS WITH OUTSIDE-OUT PATCHES AND EPSCS IN HIPPOCAMPAL-NEURONS
Autore:
RAMMES G; SWANDULLA D; SPIELMANNS P; PARSONS CG;
Indirizzi:
MERZ,DEPT PHARMACOL,ECKENHEIMER LANDSTR 100-104 D-60318 FRANKFURT GERMANY MERZ,DEPT PHARMACOL D-60318 FRANKFURT GERMANY UNIV ERLANGEN NURNBERG,INST EXPT & CLIN PHARMACOL & TOXICOL,DEPT MOL PHARMACOL D-91054 ERLANGEN GERMANY
Titolo Testata:
Neuropharmacology
fascicolo: 10-11, volume: 37, anno: 1998,
pagine: 1299 - 1320
SICI:
0028-3908(1998)37:10-11<1299:IOGANW>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; EXCITATORY SYNAPTIC TRANSMISSION; GLUTAMATE-ACTIVATED CHANNELS; NON-NMDA RECEPTORS; KAINATE RECEPTORS; TIME-COURSE; CULTURED NEURONS; RAT-BRAIN; POSTSYNAPTIC CURRENTS; MEDIATED CURRENTS;
Keywords:
OUTSIDE-OUT PATCH CLAMP; GLUTAMATE-INDUCED CURRENTS; AMPA RECEPTOR-MEDIATED EPSCS; HIPPOCAMPAL CULTURE; SLICE; GYKI 52466; NBQX; CYCLOTHIAZIDE; KINETICS; ALLOSTERIC INTERACTIONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
92
Recensione:
Indirizzi per estratti:
Citazione:
G. Rammes et al., "INTERACTIONS OF GYKI-52466 AND NBQX WITH CYCLOTHIAZIDE AT AMPA RECEPTORS - EXPERIMENTS WITH OUTSIDE-OUT PATCHES AND EPSCS IN HIPPOCAMPAL-NEURONS", Neuropharmacology, 37(10-11), 1998, pp. 1299-1320

Abstract

In outside-out patches from cultured hippocampal neurones, glutamate (1 mM) applied for 1 ms evoked currents which rose rapidly (tau(on) 451 +/- 31 mu s) to a peak and then deactivated with slower kinetics (1.95 +/- 0.13 ms). Offset time constants were significantly slower with longer application durations (tau(off) 3.10 +/- 0.9, 3.82 +/- 0.25, 4.80 +/- 0.65 and 7.56 +/- 0.65 ms with 10, 20, 100 and 500 ms applications respectively). Desensitization was complete within 100 ms with a similar rate for all application durations (4.74 +/- 0.34 ms with 100 ms applications). GYKI 52466 reduced inward peak currents with an IC50 of 11.7 +/- 0.6 mu M and had similar potency on steady-state currents to longer glutamate applications. GYKI 52466 had no significant effecton desensitization or deactivation time constants but caused a modestand significant prolongation of onset kinetics at higher concentrations. Cyclothiazide (100 mu M) potentiated steady-state currents 25-foldat 100 ms and caused a modest but significant slowing in onset kinetics (601 +/- 49 mu s with 1 ms applications) but a more pronounced prolongation of deactivation time constants (5.55 +/- 0.66 ms with 1 ms applications). In 50% of neuronal patches cyclothiazide completely eliminated desensitization. In those patches with residual desensitization,the rate was not significantly different to control (5.36 +/- 0.43 mswith 100 ms applications). Following 100 ms applications of glutamate, GYKI 52466 had IC(50)s of 11.7 +/- 1.1 mu M and 75.1 +/- 7.0 mu M inthe absence and presence of cyclothiazide (100 mu M) respectively. Onset kinetics were slowed from 400 +/- 20 mu s to 490 +/- 30 mu s by cyclothiazide (100 mu M) and then further prolonged by GYKI 52466 (100 mu M) to a double exponential function (tau(on1) 1.12 +/- 0.13 ms and tau(on2) 171.5 +/- 36.5 ms). GYKI 52466 did not re-introduce desensitization but concentration-dependently weakened cyclothiazide's prolongation of deactivation time constants (1 ms applications: 5.01 +/- 0.71, 4.47 +/- 0.80 and 2.28 +/- 0.64 ms with GYKI 52466 30, 100 and 300 mu M respectively). NBQX reduced peak current responses with an IC50 of 28.2 +/- 1.3 nM. Paradoxically, steady-state currents with 500 ms applications of glutamate were potentiated from 3.3 +/- 1.2 pA to 29.4 +/- 6.4 pA by NBQX (1 nM). Higher concentrations of NBQX then antagonized this potentiated response. The potency of NBQX in antagonizing steady-state currents to 500 ms applications of glutamate (IC50 120.9 +/- 30.2 nM) was 2-fold less than following 100 ms applications (IC50 67.7 +/- 2.6 nM). NBQX had no effect on rapid onset, desensitization or deactivation time constants. However, a slow relaxation of inhibition was seen with longer applications. NBQX was 2-5-fold less potent against inward currents in the presence of cyclothiazide (100 mu M) depending onthe application duration but had no effect on the rapid onset, desensitization or deactivation time constants. The same relaxation of inhibition was seen as with NBQX alone. NBQX (1 mu M) reduced AMPA receptor-mediated EPSC amplitude to 7 +/- 1% of control with no effect on kinetics. Cyclothiazide (330 mu M) caused a 2.8-fold prolongation of the decay time constant (control 26.6 +/- 2.2 ms, cyclothiazide 74.2 +/- 7.6 ms, n = 9). Additional application of NBQX (1 mu M) partly reversed this prolongation to 1.9 fold (47.7 +/- 2.5 ms, n = 5). These results support previous findings that cyclothiazide also allosterically influences AMPA receptor agonist/antagonist recognition sites. There were no interactions between NBQX and cyclothiazide on desensitization or deactivation time constants of glutamate-induced currents but clear interactions on EPSC deactivation kinetics. This raises the possibility that the interactions of NBQX, GYKI 52466 and cyclothiazide on AMPA-receptor-mediated EPSC kinetics observed are due to modulation of glutamate-release at presynaptic AMPA receptors. (C) 1998 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 08:15:28