Stimulation of [3H]GABA and β-[3H]Alanine Release from Rat Brain Slices by cis-4-Aminocrotonic Acid |
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Authors: | Mary Chebib Graham A. R. Johnston |
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Affiliation: | Department of Pharmacology, University of Sydney, Sydney, New South Wales, Australia |
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Abstract: | Abstract: cis -4-Aminocrotonic acid (CACA; 100 µ M ), an analogue of GABA in a folded conformation, stimulated the passive release of [3H]GABA from slices of rat cerebellum, cerebral cortex, retina, and spinal cord and of β-[3H]alanine from slices of cerebellum and spinal cord without influencing potassium-evoked release. In contrast, CACA (100 µ M ) did not stimulate the passive release of [3H]taurine from slices of cerebellum and spinal cord or of d -[3H]aspartate from slices of cerebellum and did not influence potassium-evoked release of [3H]taurine from the cerebellum and spinal cord and d -[3H]aspartate from the cerebellum. These results suggest that the effects of CACA on GABA and β-alanine release are due to CACA acting as a substrate for a β-alanine-sensitive GABA transport system, consistent with CACA inhibiting the uptake of β-[3H]alanine into slices of rat cerebellum and cerebral cortex. The observed K i for CACA against β-[3H]alanine uptake in the cerebellum was 750 ± 60 µ M . CACA appears to be 10-fold weaker as a substrate for the transporter system than as an agonist for the GABAc receptor. The effects of CACA on GABA and β-alanine release provide indirect evidence for a GABA transporter in cerebellum, cerebral cortex, retina, and spinal cord that transports GABA, β-alanine, CACA, and nipecotic acid that has a similar pharmacological profile to that of the GABA transporter, GAT-3, cloned from rat CNS. The structural similarities of GABA, β-alanine, CACA, and nipecotic acid are demonstrated by computer-aided molecular modeling, providing information on the possible conformations of these substances being transported by a common carrier protein. |
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Keywords: | GABA transporters cis-4-Aminocrotonic acid β-Alanine Nipecotic acid CNS Release |
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