Abstract
The ability of two conformationally restricted analogues of L-glutamate to function as nontransportable inhibitors of plasma membrane L-glutamate transport was investigated in primary cultures of cerebellar granule cells and cortical astrocytes. L -trans- Pyrrolidine-2,4- dicarboxylic acid ( L -trans PDC ) and cis-1-aminocyclobutane-1,3-dicarboxylic acid ( cis-ACBD) behaved as linear competitive inhibitors of the uptake of d-[ 3H]aspartate (used as a non-metabolizable analogue of L-glutamate) exhibiting K i values between 40 and 145 μm; L -trans- PDC being the more potent inhibitor in each preparation. However, both L -trans- PDC and cis-ACBD, over a concentration range of 1 μM-5 mM, dose-dependently stimulated the release of exogenously supplied d-[ 3H]aspartate from granule cells maintained in a continuous superfusion system. The stimulated release was independent of extracellular calcium ions; essentially superimposable dose-response profiles being obtained in the absence and presence of 1.3 mM CaCl 2 and yielding ec 50 values of 16–25 μM and 180–220 μM for L -trans- PDC and cis-ACBD, respectively. Stimulated release of d-[ 3H]aspartate was unaffected by either 300 μm d-(−)-2-amino-5-phosphonopentanoi acid [ d-APV; a selective antagonist of the N-methyl- d-aspartate (NMDA) receptor] or by 25 μM 6-cyano-7-nitroquinoxaline-2,3-dione [CNQX; a selective antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor]. The release of d-[ 3H] aspartate following stimulation by either L -trans- PDC or cis-ACBD was however markedly attenuated following substitution in the superfusion medium of sodium ions by choline ions. Taken together, these results support an action of L -trans- PDC and cis-ACBD consistent with that of being competitive substrates rather than non-transportable blockers of the plasma membrane L-glutamate uptake system.
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