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Evidence for a Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters

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Abstract

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.

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Acknowledgments

We thank Dr. Donald Loo and Ms. Rachel Sanchez for carefully reading the manuscript, and Ms. Renee J. Estephan and Ms. Elizabeth Michaela Lizhar for technical assistance. This work was supported in part by a U.S. National Institute of General Medical Sciences Grant awarded to S.E. (SC1GM086344).

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The authors declare that they have no conflict of interest.

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  1. Biological Sciences Department, California State Polytechnic University, 3801 West Temple Avenue, Pomona, CA, 91768-4032, USA

    Samantha L. Willford, Cynthia M. Anderson, Shelly R. Spencer & Sepehr Eskandari

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  1. Samantha L. Willford
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Willford, S.L., Anderson, C.M., Spencer, S.R. et al. Evidence for a Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters. J Membrane Biol 248, 795–810 (2015). https://doi.org/10.1007/s00232-015-9797-6

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