Stimulation of [3H]GABA and β‐[3H]Alanine Release from Rat Brain Slices by cis‐4‐Aminocrotonic Acid

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Abstract
Cis-4-Aminocrotonic acid (CACA; 100 µM), an analogue of GABA in a folded conformation, stimulated the passive release of ( 3 H)GABA from slices of rat cerebellum, cerebral cortex, retina, and spinal cord and of β- ( 3 H)alanine from slices of cerebellum and spinal cord without influencing potassium-evoked release. In contrast, CACA (100 µM) did not stimulate the passive release of ( 3 H)taurine from slices of cerebellum and spinal cord or of D- ( 3 H))aspartate from slices of cerebellum and did not influence potassium-evoked release of ( 3 H)taurine from the cerebellum and spinal cord and D-( 3 H)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-( 3 H)alanine into slices of rat cerebellum and cerebral cortex. The observed Ki for CACA against β-( 3 H)alanine uptake in the cerebellum was 750 ± 60 µM. CACA appears to be 10-fold weaker as a substrate for the transporter system than as an agonist for the GABA C 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

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