Lecture_10-GABA_Lecture

Amino butyric acid meet criterion for a

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-amino-butyric acid) • Meet criterion for a neurotransmitter: 1) synthesized within neurons 2) packaged and stored within neurons 3) released from neurons upon depolarization 4) also have transporters for reuptake ***all of the above also true for astrocytes
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-Aminobutyric acid (GABA) - GAD (glutamate decarboxylase) converts glutamate to GABA (requires pyridoxal phosphate as cofactor) -enriched in cytosol and synaptosomes (terminals) -2 isoforms GAD65* and GAD67 (90% sequence homology) - GABA-T (GABA aminotransferase or GABA transaminase) -mitochondrial enzyme; cytosol of neurons and astrocytes -transfers the amino group from GABA to -ketoglutarate -products are succinic semialdehyde (gets converted into succinate) and glutamate
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Affecting GABA synthesis -rate of GABA synthesis in vivo is low (below the rate of GAD activity) - in vivo glutamate levels (10 mM) way above Km for GAD (0.2-1.2 mM) so GAD is saturated? GAD activity does not appear to be regulated by precursor levels -increasing glutamate levels does not lead to an increase in GABA levels -50% of GAD in brain exists as an “ apoenzyme ” (inactive) while 50% of GAD exists as a haloenzyme ” (active; bound to co-factors) -GABA promotes cycling from haloenzyme to apoenzyme - GABA is a competitive inhibitor of glutamate binding site on GAD -inhibiting co-factor binding to GAD reduces GABA levels induces seizures
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Affecting GABA catabolism -inhibiting GABA-T elevates GABA levels GABA-T Inhibitors - vigabatrin (GVG or -vinyl GABA; irreversible) - AOAA (aminoooxyacetic acid) -gabaculine sedative and anti-convulsant properties
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amino butyric acid Meet criterion for a neurotransmitter 1...

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