Abstract

In vitro addition of glutamate (GLU) resulted in a dose-dependent inhibition of protein synthesis in synaptosomes from adult rat brain cortex. There was significant (20-25%) inhibition at 25 ?M GLU and a maximum (30-50%) inhibition was observed at [GLU] ? 200 ?M. The excitatory amino acids, N- methyl- d -aspartic acid (NMDA), kainic acid (KA), quinolinic acid (QUIN) and selected non-excitatory amino acids did not markedly inhibit protein synthesis at all concentrations tested. On the other hand, aspartic acid (ASP), ibotenic acid (IBO), quisqualic acid (QA) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) produced a significant but apparently less potent inhibition than GLU. In the presence of AMPA plus ASP or GLU (500 ?M each), protein synthesis inhibition was equivalent to the maximum effect of GLU alone. However, only partial additive effects were observed with high concentrations of AMPA + IBO or AMPA + QA. In the presence of 200 ?M ouabain, synergistic GLU inhibition was not observed suggesting that GLU specifically inhibited the sodium-dependent, ouabain-sensitive component of synaptosomal protein synthesis. The inhibitory action of GLU is not dependent on externally added Ca(2+) or Cl(?). Supplementation with 5 mM MgCl(2) or 1.0 mM GLU antagonists, 2-amino-5-phosphonovaleric acid (AP5), 2-amino-7-phosphonoheptanoic acid (AP7), ?-glutamylglycine (?-DGG), kynurenic acid (KYN), MK-801, l-glutamic acid diethyl ester (GDEE) and 6-cyano-7-nitro quinoxaline-2,3-dione (CNQX) did not protect the synaptosomes from 50 ?M GLU. Inhibiting glutamate uptake or phosphoinositide metabolism with 1 mM dihydrokainic acid (DHK) and 5 mM LiCl(2), respectively, was also non-protective. These data suggest that GLU and other excitatory amino acids (EAA) specifically inhibit synaptosomal protein synthesis. The inhibitory effect is partially associated with activation of QA-preferring receptors which may not be coupled to phosphoinositide metabolism. A possible candidate might be the AMPA specific QA receptor located in the postsynaptic density which is in close proximity to rosettes of polyribosomes. In addition, there is a GLU-sensitive, QA-resistant component of synaptosome protein synthesis which does not appear to be dependent on activation of any of the known pharmacologically defined GLU receptor subtypes.

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