Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters

The purpose of this review is to highlight recent evidence in support of a 3 Na⁺: 1 Cl^-: 1 GABA coupling stoichiometry for plasma membrane GABA transporters (SLC6A1 , SLC6A11 , SLC6A12 , SLC6A13 ) and how the revised stoichiometry impacts our understanding of the contribution of GABA transporters to GABA homeostasis in synaptic and extrasynaptic regions in the brain under physiological and pathophysiological states. Recently, our laboratory probed the GABA transporter stoichiometry by analyzing the results of six independent measurements, which included the shifts in the thermodynamic transporter reversal potential caused by changes in the extracellular Na⁺, Cl^-, and GABA concentrations, as well as the ratio of charge flux to substrate flux for Na⁺, Cl^-, and GABA under voltage-clamp conditions. The shifts in the transporter reversal potential for a tenfold change in the external concentration of Na⁺, Cl^-, and GABA were 84 ± 4, 30 ± 1, and 29 ± 1 mV, respectively. Charge flux to substrate flux ratios were 0.7 ± 0.1 charges/Na⁺, 2.0 ± 0.2 charges/Cl^-, and 2.1 ± 0.1 charges/GABA. We then compared these experimental results with the predictions of 150 different transporter stoichiometry models, which included 1-5 Na⁺, 0-5 Cl^-, and 1-5 GABA per transport cycle. Only the 3 Na⁺: 1 Cl^-: 1 GABA stoichiometry model correctly predicts the results of all six experimental measurements. Using the revised 3 Na⁺: 1 Cl^-: 1 GABA stoichiometry, we propose that the GABA transporters mediate GABA uptake under most physiological conditions. Transporter-mediated GABA release likely takes place under pathophysiological or extreme physiological conditions.