ARGININE AVAILABILITY CONTROLS THE N-METHYL-D-ASPARTATE-INDUCED NITRIC-OXIDE SYNTHESIS - INVOLVEMENT OF A GLIAL-NEURONAL ARGININE TRANSFER

The neuronal nitric oxide (NO) synthase generates NO from arginine. NO mediates its physiological effects mainly by stimulating the synthesi s of cyclic GMP. We have investigated the role of the arginine availab ility on the NMDA-induced cyclic GMP accumulation in immature rat brai n slices. The effect of NMDA was blocked by the inhibitor of the NO sy nthase, N-G-nitro-L-arginine, and by the antagonist of ionotropic non- NMDA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). This inhi bition was not due to a direct interaction of CNQX with the NMDA recep tor, and it was overcome by the presence of exogenously applied argini ne. CNQX also blocked the NMDA-evoked release of [H-3]arginine from ce rebellar slices. Moreover, the arginine uptake inhibitor L-lysine redu ced the cyclic GMP response to NMDA significantly. Therefore, the extr acellular arginine availability, which is dependent on the activation of ionotropic non-NMDA receptors, determines the rate of the NO biosyn thesis by the neuronal NO synthase. Together with the reported release of arginine from glial cells upon activation of glial ionotropic non- NMDA receptors and the predominant glial localization of arginine, the se data provide the first evidence of an essential role of the arginin e transfer from glial cells to neurons for the biosynthesis of NO.