Identification and selective inhibition of the channel mode of the neuronal 
GABA transporter 1

Krause, Stephan M.; Schwarz, Wolfgang

doi:10.1124/mol.105.013870

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Identification and selective inhibition of the channel mode of the neuronal GABA transporter 1

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Krause, Stephan M.
Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Schwarz, Wolfgang
Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Krause, S. M., & Schwarz, W. (2005). Identification and selective inhibition of the channel mode of the neuronal GABA transporter 1. Molecular Pharmacology, 68(6), 1728-1735. doi:10.1124/mol.105.013870.

Cite as: https://hdl.handle.net/21.11116/0000-0008-2E0D-8

Abstract

The function of GAT1, the transporter for the inhibitory neurotransmitter GABA, is characterized by expression in Xenopus laevis oocytes and measurements of GABA-induced uptake of [³H]GABA, ²²Na⁺, and ³⁶Cl^-, and GABA-evoked currents under voltage-clamp conditions. N-[4,4-Diphenyl-3-butenyl]-nipecotic acid (SKF-89976-A), a specific inhibitor of GAT1, is used in our system as a pharmacological tool. The GABA-evoked current can be decomposed into a transport current, which is coupled to the GABA uptake, and a transmitter-gated current, which is uncoupled from the GABA uptake. The transport current results from a fixed stoichiometry of 1 GABA/2 Na⁺/1 Cl^- transported during each cycle, as determined by radioactive tracer flux measurements. The transmitter-gated current is mediated by an Na⁺-conductance pathway. As a competitive inhibitor for GABA uptake, SKF-89976-A can separate the two current components. The GABA uptake is blocked with a K_I value of approximately 7 μM, whereas the uncoupled transmitter-gated current is inhibited with a K_I value of approximately 0.03 μM. Thus, the results of this study not only identify the transport mode and the channel mode of GAT1 but also raise the possibility of separating these components in a physiological environment.