Dynamic equilibrium of neurotransmitter transporters: Not just for reuptake anymore

Many electrophysiologists view neurotransmitter transporters as tiny vacuum cleaners, operating continuously to lower extracellular neurotransmitter concentration to zero. However, this is not consistent with their known behavior, instead only reducing extracellular neurotransmitter concentration to a finite, nonzero value at which an equilibrium is reached. In addition, transporters are equally able to go in either the forward or reverse direction, and when they reverse, they release their substrate in a calcium-independent manner. Transporter reversal has long been recognized to occur in response to pathological stimuli, but new data demonstrate that some transporters can also reverse in response to physiologically relevant stimuli. This is consistent with theoretical calculations that indicate that the reversal potentials of GABA and glycine transporters are close to the resting potential of neurons under normal conditions and that the extracellular concentration of GABA is sufficiently high when the GABA transporter is at equilibrium to tonically activate high-affinity extrasynaptic GABA(A) receptors. The equilibrium for the GABA transporter is not static but instead varies continuously as the driving force for the transporter changes. We propose that the GABA transporter plays a dynamic role in control of brain excitability by modulating the level of tonic inhibition in response to neuronal activity.