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J. Biol. Chem., Vol. 279, Issue 21, 21774-21778, May 21, 2004

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The M₃ Receptor-mediated K⁺ Current (I_KM3), a G_q Protein-coupled K⁺ Channel^*

Hong Shi¶, Huizhen Wang, Baofeng Yang||, Donghui Xu**, and Zhiguo Wang

From the Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada, the Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7 Canada, the ^||Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086 P. R. China, and the ^**School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, People's Republic of China

Stimulation of muscarinic acetylcholine receptors (mAChRs) can activate an inward rectifier K⁺ current (I_KACh), which is mediated by the M₂ subtype of mAChR in cardiac myocytes. Recently, a novel delayed rectifier-like K⁺ current mediated by activation of the cardiac M₃ receptors (designated I_KM3) was identified, which is distinct from I_KACh and other known K⁺ currents. While I_KACh is known to be a G_i protein-gated K⁺ channel, the signal transduction mechanisms for I_KM3 activation remained unexplored. We studied I_KM3 with whole-cell patch clamp and macropatch clamp techniques. Whole cell I_KM3 activated by choline persisted with minimal rundown over 2 h in presence of internal GTP. When GTP was replaced by guanyl-5'-yl thiophosphate, I_KM3 demonstrated rapid and extensive rundown. While I_KACh (induced by ACh) was markedly reduced in cells pretreated with pertussis toxin, I_KM3 was unaltered. Intracellular application of antibodies targeting -subunit of G_i/o protein suppressed I_KACh without affecting I_KM3. Antibodies targeting the N and the C terminus, respectively, of G_q protein -subunit substantially depressed I_KM3 but failed to alter I_KACh. The antibody against -subunits of G proteins inhibited both I_KACh and I_KM3. I_KM3 activated by choline in the cell-attached mode of macropatches persisted in the cell-free configuration. Application of purified G_q protein -subunit or -subunit of G proteins or guanosine 5'-O-(thiotriphosphate) to the internal solution activated I_KM3-like currents in inside-out patches. Our findings revealed a novel aspect of receptor-channel signal transduction mechanisms, and I_KM3 represents the first G_q protein-coupled K⁺ channel. We propose that the G protein-coupled K⁺ channel family could be divided into two subfamilies: G_i protein-coupled K⁺ channel subfamily and G_q protein-coupled K⁺ channel subfamily.

Received for publication, March 4, 2004 , and in revised form, March 24, 2004.

^* This work was supported in part by the Heart and Stroke Foundation of Quebec and the Fonds de la Recherche de l'Institut de Cardiologie de Montreal (awarded to Z. W.). 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.

These two contributed equally to this work and are both Research fellows of the Canadian Institute of Health Research during the study.

^¶ Current address: Bristol Myers Squibb Co., Pharmaceutical Research Inst., P. O. Box 5400, 311 Pennington-Rocky Hill Rd., Princeton, NJ 08543.

A research scholar of the Fonds de Recherche en Sante de Quebec. To whom correspondence should be addressed: Research Center, Montreal Heart Inst., 5000 Belanger East, Montreal, Quebec H1T 1C8, Canada. Tel.: 514-376-3330 (ext. 3517); Fax: 514-376-1355; E-mail: wangz{at}icm.umontreal.ca.

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