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J. Biol. Chem., Vol. 279, Issue 33, 34240-34249, August 13, 2004

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The Sensitivity of G Protein-activated K⁺ Channels toward Halothane Is Essentially Determined by the C Terminus^*

Sergej Milovic, Bibiane Steinecker-Frohnwieser, Wolfgang Schreibmayer, and Lukas G. Weigl¶

From the Medical University of Vienna, Department of Anesthesia and Intensive Care Medicine (B), Währinger Gürtel 18–20, A-1090 Vienna, Austria and the Institute for Medical Physics and Biophysics, Medical University of Graz, A-8010 Graz, Austria

G protein-activated K⁺ channels (GIRKs or Kir3.x) are targets for the volatile anesthetic, halothane. When coexpressed with the m₂ acetylcholine (ACh) receptor in Xenopus oocytes, agonist-activated GIRK1^F137S- and GIRK2-mediated currents are inhibited by halothane, whereas in the absence of ACh, high concentrations of halothane induce GIRK1^F137S-mediated currents. To elucidate the molecular mechanism of halothane action on GIRK currents of different subunit compositions, we constructed deletion mutants of GIRK1^F137S (GIRK1^363*) and GIRK2 (GIRK2³⁵⁶) lacking the C-terminal ends, as well as chimeric GIRK channels. Mutated GIRK channels showed normal currents when activated by ACh but exhibited different pharmacological properties toward halothane. GIRK2³⁵⁶ showed no sensitivity against the inhibitory action of halothane but was activated by halothane in the absence of an agonist. GIRK1^363* was activated by halothane more efficiently. Currents mediated by chimeric channels were inhibited by anesthetic concentrations that were at least 30-fold lower than those necessary to decrease GIRK2 wild type currents. Glutathione S-transferase pulldown experiments did not show displacement of bound G by halothane, indicating that halothane does not interfere with G binding. Single channel experiments revealed an influence of halothane on the gating of the channels: The agonist-induced currents of GIRK1 and GIRK2, carried mainly by brief openings, were inhibited, whereas higher concentrations of the anesthetic promoted long openings of GIRK1 channels. Because the C terminus is crucial for these effects, an interaction of halothane with the channel seems to be involved in the mechanism of current modulation.

Received for publication, March 29, 2004 , and in revised form, June 1, 2004.

^* This work was supported by Grant 8266 from the Oesterreichische Nationalbank (to L. G. W.), Austrian Research Foundation Grants P17702-B09 (to L. G. W.), T124-B04 (to B. S.-F.), and SFB007/F708 (to W. S.), and Austrian Ministry of Science Grant UGP4 (to W. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 43-1-40400-4147; Fax: 43-1-40400-6422; E-mail: lukas.weigl{at}univie.ac.at.

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