Novel Properties of a Mouse γ-Aminobutyric Acid Transporter (GAT4)

Novel Properties of a Mouse γ-Aminobutyric Acid Transporter (GAT4) We expressed the mouse γ-aminobutyric acid (GABA) transporter GAT4 (homologous to rat/human GAT-3) in Xenopus laevis oocytes and examined its functional and pharmacological properties by using electrophysiological and tracer uptake methods. In the coupled mode of transport (Na+/Cl−/GABA cotransport), there was tight coupling between charge flux and GABA flux across the plasma membrane (2 charges/GABA). Transport was highly temperature-dependent with a temperature coefficient (Q 10) of 4.3. The GAT4 turnover rate (1.5 s−1; −50 mV, 21°C) and temperature dependence suggest physiological turnover rates of 15–20 s−1. No uncoupled current was observed in the presence of Na+. In the absence of external Na+, GAT4 exhibited two distinct uncoupled currents. (i) A Cl− leak current ( $ I_{{\rm leak}}^{{\rm Cl}} $ ) was observed when Na+ was replaced with choline or tetraethylammonium. The reversal potential of ( $I_{{\rm leak}}^{{\rm Cl}} $ ) followed the Cl− Nernst potential. (ii) A Li+ leak current ( $I_{{\rm leak}}^{{\rm{Li}}} $ ) was observed when Na+ was replaced with Li+. Both leak currents were inhibited by Na+, and both were temperature-independent (Q 10 ≈ 1). The two leak modes appeared not to coexist, as Li+ inhibited ( $I_{{\rm leak}}^{{\rm Cl}} $ ). The results suggest the existence of cation- and anion-selective channel-like pathways in GAT4. Flufenamic acid inhibited GAT4 Na+/C1−/GABA cotransport, $I_{{\rm leak}}^{{\rm{Li}}}$ , and $I_{{\rm leak}}^{{\rm Cl}}$ , (K i ≈ 30 μM), and the voltage-induced presteady-state charge movements (K i ≈ 440 μM). Flufenamic acid exhibited little or no selectivity for GAT1, GAT2, or GAT3. Sodium and GABA concentration jumps revealed that slow Na+ binding to the transporter is followed by rapid GABA-induced translocation of the ligands across the plasma membrane. Thus, Na+ binding and associated conformational changes constitute the rate-limiting steps in the transport cycle. The Journal of Membrane Biology Springer Journals

Novel Properties of a Mouse γ-Aminobutyric Acid Transporter (GAT4)

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Copyright © 2005 by Springer Science+Business Media, Inc.
Life Sciences; Human Physiology; Biochemistry, general
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