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Glutamic acid decarboxylases and GABA transporters determine GABA trafficking and function

Glutamic acid decarboxylases and GABA transporters determine GABA trafficking and function

Society for Neuroscience Abstracts 27(2): 1838

We hypothesize that together, GABA-synthesizing and GABA-transporting molecules determine GABA location, which is fundamental to its role. Two glutamic acid decarboxylases (GADs) synthesize GABA. We believe that GAD65 makes GABA that is packaged by the vesicular GABA transporter (vGAT) for exocytotic release. GAD67, found throughout the cytosol, produces cytosolic GABA, which can exit the cell via the plasma membrane GABA transporter (GAT). Exocytotically released GABA results in high synaptic concentrations for brief time periods. GAT-mediated GABA release may have different spatial and temporal constraints. High-sensitivity GABA detectors may elucidate these differences. We designed cDNA constructs with GAD65, GAD67, vGAT or GAT fused to color variants of GFP. Transient transfection of our constructs into fibroblast and neural cells yields proteins detectable by fluorescent microscopy. GAD-transfected cells produce enzymatically active GADs and micromoles of GABA. We can stimulate exocytotic or carrier-mediated GABA release and determine how GAD67-synthesized vs. GAD65-synthesized GABA exits the cell. We quantified GABA by HPLC, but this technique lacks the resolution required to distinguish vesicular and paracrine GABA release. We are designing sol-gel monolith and fiber-optic GABA sensors based on our glutamate sensors that detect uM to mM glutamate over seconds. Monolith sensors measure time-resolved release from cell populations. Fiber-optic sensors provide spatial as well as temporal information.

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Accession: 034998015

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