GABA--the quintessential neurotransmitter: electroneutrality, fidelity, specificity, and a model for the ligand binding site of GABAA receptors.

Alone of the known neurotransmitters, GABA is an electroneutral zwitterion (pI = 7.3) at physiological pH. This confers the highest probability of successfully traversing densely packed synaptic gaps without interacting electrostatically with charged entities enroute, making GABA a high fidelity neurotransmitter. Inhibitory tone in the nervous system is coordinately coupled with physiological activity by means of the GABA system, acidification increasing GABA formation and its Cl- channel-opening efficacy, while decreasing its removal by transport and metabolic degradation. The above, together with diminution upon acidification of the postsynaptic efficacy of glutamate on excitatory NMDA receptors constitutes a sensitively responsive mechanism by which protons control levels of neural activity, locally and globally. A model made of the GABA binding site of GABAA receptors based on H-bond and hydrophobic interactions makes it seem unlikely that any other substance known to occur in nerve tissue would give rise to a high noise level at GABAA receptors.