Dynamic Equilibrium of Neurotransmitter Transporters: Not Just for Reuptake Anymore

Abstract

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 GABAA 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.

GABAA receptor subtypes: the “one glass of wine” receptors

“…However, Carta et al (2004) interpreted this as being caused by increased GABA release, due to their observation that 1 µM tetrodotoxin (TTX, a blocker of voltage-gated neuronal sodium channels) abolished EtOH enhancement of tonic currents. However, such experiments are difficult to interpret because TTX reduces extracellular [GABA], at least partly due to block of GABA release, but there are likely other important non-vesicular GABA sources (Richerson and Wu, 2003;Wu et al, 2006). In fact, in the presence of constant 300 nM GABA, 1 µM TTX did not abolish EtOH enhancement of tonic currents in cerebellar granule cells in our hands (Hanchar et al, 2005), fully consistent with direct actions of alcohol on these receptor subtypes.…”

“…However, the importance of a constantly active (tonic) form of GABAergic inhibition is more and more recognized as a very important form of inhibition (Mody, 2001;Farrant and Nusser, 2005). Tonic inhibition is due to highly GABAsensitive receptors activated by ambient GABA present in the brain thought to be in the range of 100 nM to 1 µM (Tossman et al, 1986;Richerson and Wu, 2003;Santhakumar et al, 2006). While, some tonic GABA currents can be mediated by γ2 subunit-containing receptors (Caraiscos et al, 2004), more often these currents are mediated by receptors that contain the δ subunit, shown to excluded from synapses (Nusser et al, 1998) or located perisynaptically (Wei et al, 2003).…”

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

“…The GABA A receptors generating the tonic current and modulated by GLP-1 receptor signaling in the postsynaptic neuron are high-affinity, extrasynaptic GABA A receptors that are activated by the very low, ambient GABA concentrations present around the neurons. Where the GABA originates from is not clear, but mechanisms involving nonvesicular release (40)(41)(42) such as reversal of GABA transporters or release of GABA from astrocytes have been proposed. That pre-and postsynaptic mechanisms can regulate tonic GABA A receptor-mediated currents in hippocampal neurons is in accordance with previous reports (33,35,36,39).…”

Misuse and Abuse of Pregabalin and Gabapentin: Cause for Concern?

“…Similarly, at relevant clinical concentrations, gabapentin does not bind to GABA A , GABA B , benzodiazepine or glycine/NMDA receptors [4]. Gabapentin may exert its GABAergic effects through both modulation of GABA metabolism and reversal of neuronal/ glial amino acid transporters, with GABA being released for interaction with extra-synaptic GABA receptors [20,21]. Indeed, gabapentin 900-mg administration to healthy human subjects resulted in an average increase in GABA concentration of about 56 % (6.9-91.0 %), with druginduced changes in GABA levels being inversely correlated to the individual's baseline GABA levels [22].…”