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Stimulation of [ 3 H]GABA and β‐[ 3 H]Alanine Release from Rat Brain Slices by cis ‐4‐Aminocrotonic Acid
Author(s) -
Chebib Mary,
Johnston Graham A. R.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68020786.x
Subject(s) - cerebellum , nipecotic acid , chemistry , gaba transporter , alanine , taurine , spinal cord , biochemistry , biology , endocrinology , neuroscience , gabaergic , receptor , neurotransmitter , amino acid
cis ‐4‐Aminocrotonic acid (CACA; 100 µ M ), 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 µ M ) 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 K i for CACA against β‐[ 3 H]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 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 common carrier protein.