Plasma membrane γ-aminobutyric acid (GABA) transporters (GATs) are electrogenic transport proteins that couple the cotranslocation of Na(+), Cl(-), and GABA across the plasma membrane of neurons and glia. A fundamental property of the transporter that determines its ability to concentrate GABA in cells and, hence, regulate synaptic and extra-synaptic GABA concentrations, is the ion/substrate coupling stoichiometry. Here, we scrutinized the currently accepted 2 Na(+):1 Cl(-):1 GABA stoichiometry because it is inconsistent with the measured net charge translocated per co-substrate (Na(+), Cl(-), and GABA). We expressed GAT1 and GAT3 in Xenopus laevis oocytes and utilized thermodynamic and uptake under voltage-clamp measurements to determine the stoichiometry of the GABA transporters. Voltage-clamped GAT1-expressing oocytes were internally loaded with GABA, and the reversal potential (V rev) of the transporter-mediated current was recorded at different external concentrations of Na(+), Cl(-), or GABA. The shifts in V rev for a tenfold change in the external Na(+), Cl(-), and GABA concentration were 84 ± 4, 30 ± 1, and 29 ± 1 mV, respectively. To determine the net charge translocated per Na(+), Cl(-), and GABA, we measured substrate fluxes under voltage clamp in cells expressing GAT1 or GAT3. Charge flux to substrate flux ratios were 0.7 ± 0.1 charge/Na(+), 2.0 ± 0.2 charges/Cl(-), and 2.1 ± 0.1 charges/GABA. Altogether, our results strongly suggest a 3 Na(+):1 Cl(-):1 GABA coupling stoichiometry for the GABA transporters. The revised stoichiometry has important implications for understanding the contribution of GATs to GABAergic signaling in health and disease.

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.

Objective To review current multidisciplinary care practices in patients with Tourette syndrome (TS). Background Individuals with TS can have multiple symptoms and comorbidities and require treatment to encompass all of their needs. A multidisciplinary research or care model approaches the situation/problem from all sides and uses multiple perspectives. Methods A database search of Medline (using Pubmed), PsychINFO, and Scopus was performed using keywords related to multidisciplinary care and TS. The authors then screened the results for relevant information using a standardized extraction form to collect data. Next, relevant codes from text analysis were extracted with a final list agreed on with author consensus. Finally, we inferred common themes. Results The search revealed 2304 citations, and 87 were selected for full‐text analysis. One additional article was identified by manual search. Thirty‐one citations were deemed relevant. Multidisciplinary team members typically included a psychiatrist or child psychiatrist, a neurologist or child neurologist, and a psychologist or therapist at the core. Four primary benefits were associated with multidisciplinary care: establishing the diagnosis, managing the complexity of TS and its associated comorbidities, averting complications, and evaluating advanced therapies. Limitations include possible poor team dynamics and rigidity in the approach leading to an algorithmic treatment plan. Conclusions A multidisciplinary care model for TS is the preferred model advocated by patients, physicians, and organizations. This scoping review reveals that the impetus for multidisciplinary care rests on four primary benefits, but there is a lack of empirical evidence for defining and evaluating its use.

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