Summary

In the 50 years since its identification as a neurotransmitter, GABA has emerged as a major force in normal CNS function, development, and disease. In addition to neurotransmission, GABA can provide energy through the GABA shunt and can mediate developmental events. Outside of the nervous system, GABA is involved with pancreatic glucagon release and is required for palate formation.

The variety of functions that GABA can perform may be governed in part by the different location and regulation of the two GABA-synthesizing enzymes. GAD65 appears to synthesize GABA largely for neurotransmission, whereas GAD67 synthesizes GABA that is available for the GABA shunt and also for release directly through GAT. The manner by which GABA leaves the cell may also be important in determining its function. GABA released via exocy-tosis is largely confined to the synapse, whereas that released through GAT is available to extrasynaptic receptors.

GABA receptors are an additional modulator of GABA function. Different subunit compositions impart different sensitivity, kinetics, and location. The GABAa receptor can confer inhibition or excitation, depending on the chloride gradient across the membrane. The GABAB receptor can exert both presynaptic and postsynaptic effects. The diversity of GABA actions is due in no small part to the great variation within the GABA receptor family.

GABA is the major inhibitory neurotransmitter and changes in GABA signaling have widespread effects. A role for GABA dysfunction can be argued even in diseases for which the primary pathology lies elsewhere. The molecules that synthesize, transport, respond to, and degrade GABA are all potential targets for therapy. Drugs that can selectively activate specific receptor subtypes or that can interfere with the kinetics of GABA transport and degradation will certainly be helpful in treating GABA-related diseases. Alternate approaches, including gene therapy, to control local GABA concentrations are also promising. Our understanding of the mechanisms of GABA regulation and signaling will therefore lead to new and effective therapies for a variety of diseases.

See Also the Following Articles

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