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This Article Full Text Full Text (PDF) All Versions of this Article: 586/11/2743    most recent jphysiol.2008.153346v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Xie, A. Articles by Qian, H. PubMed PubMed Citation Articles by Xie, A. Articles by Qian, H. Related Collections Neuroscience

¹ Departments of Ophthalmology and Visual Sciences
² Biological Sciences
³ Anatomy and Cell Biology
⁴ Physiology & Biophysics, University of Illinois College of Medicine, 1855 West Taylor Street, Chicago, IL 60612, USA

We tested the effects of cyclothiazide (CTZ), an agent used to block desensitization of AMPA-type glutamate receptors, on heterologously expressed GABA_C receptors formed by homomeric subunits. CTZ inhibition of GABA_C receptors was subunit specific; it produced a dose-dependent reduction of the GABA-elicited current on homomeric 2 receptors with an IC₅₀ of about 12 µM, but had no significant effect on homomeric 1 receptors. This differential sensitivity was attributable to a single amino acid located on the second transmembrane domain of the subunits. Mutating the residue at this position from serine to proline on the 2 subunit eliminated CTZ sensitivity, whereas switching proline to serine on the 1 subunit made the receptor CTZ sensitive. The inhibitory properties of CTZ were consistent with its action as a channel blocker on the receptors formed by 2 subunits. The effect showed a small degree of voltage dependence, and was due mainly to a non-competitive mechanism that reduced the maximum response elicited by GABA. In addition, the prominent membrane current rebound when co-application of GABA and CTZ was terminated suggests that the binding site for CTZ on the GABA_C receptor is distinct from that for GABA, and that CTZ acts as a non-competitive antagonist on the GABA_C receptor. CTZ inhibited the open channel of the GABA_C receptor with a time constant of about 0.4 s, but the kinetics were 10-fold slower when GABA is absent. The ability of CTZ to interact with various types of neurotransmitter receptors indicates that the drug has multiple actions in the CNS.

(Received 4 March 2008; accepted after revision 10 April 2008; first published online 17 April 2008)
Corresponding author H. Qian: Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 W. Taylor Street, Chicago, IL 60612, USA. Email: hqian{at}uic.edu