The effect of glutamate on the accumulation of ( 3 H )inositol phosphates was examined in oligodendrocyte progenitor cultures prepared from rat brains. Glutamate, and the analogues α -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate, caused a concentration- and time-dependent increase in ( 3 H )inositol trisphosphate (IP 3 ) formation and the effect was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a competitive AMPA and kainate receptor antagonist. Similarly, the more selective, noncompetitive antagonist of AMPA receptors, 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), significantly reduced the effect of both AMPA and kainate. In contrast, antagonists of N -methyl- d -aspartate (NMDA) receptor, (5 R ,10 S )-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine (MK-801) and R (−)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), and antagonists of metabotropic receptors, l (+)-2-amino-3-phosphono-propanoic acid ( l -AP3) and α -methyl-4-carboxyphenylglycine (MCPG), were ineffective. These results suggest that the effect of glutamate on ( 3 H )IP 3 accumulation is mediated through ionotropic AMPA receptors. Cyclothiazide, an inhibitor of AMPA receptor desensitization, strongly potentiated the AMPA and kainate-stimulated ( 3 H )IP 3 formation as well as the uptake of 45 Ca 2+ in line with the previous findings. 45 Ca 2+ uptake evoked by AMPA or kainate, in combination with cyclothiazide, was also prevented by both CNQX and GYKI 52466. Glutamate-stimulated ( 3 H )IP 3 accumulation was prevented by EGTA, suggesting a requirement for extracellular calcium. Pre-incubation with the voltage-gated Ca 2+ channel blockers, diltiazem, nifedipine and CdCl 2 , partially prevented the glutamate-induced ( 3 H )IP 3 accumulation as well as 45 Ca 2+ uptake. Similarly, the Na + /Ca 2+ exchanger blockers benzamil and 3,4-dichlorobenzamil reduced significantly kainate-stimulated 45 C a 2+ uptake. These data indicate that glutamate-induced ( 3 H )IP 3 accumulation is triggered by calcium influx via AMPA receptors, voltage-gated calcium channels and the Na + /Ca 2+ exchanger operating in reverse mode.
European Journal of Pharmacology – Elsevier
Published: Nov 12, 1997
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