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First published on September 8, 2005; DOI: 10.1124/mol.105.013870

0026-895X/05/6806-1728-1735$20.00
Mol Pharmacol 68:1728-1735, 2005

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Identification and Selective Inhibition of the Channel Mode of the Neuronal GABA Transporter 1

Stephan Krause1, and Wolfgang Schwarz

Max-Planck-Institute for Biophysics, Frankfurt am Main, Germany; and Max-Planck Guest Laboratory at the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

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 KI value of approximately 7 µM, whereas the uncoupled transmitter-gated current is inhibited with a KI 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.

Received April 19, 2005; accepted September 7, 2005

Address correspondence to: Dr. Stephan Krause, University of Oulu, Department of Physical Sciences, Division of Biophysics, Linnanmaa, 90014 Oulun Yliopisto, Finland. E-mail: stephan.krause{at}oulu.fi




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