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J Biol Chem, Vol. 275, Issue 17, 12537-12545, April 28, 2000

Novel Inhibition of G-activated Potassium Currents Induced by M₂ Muscarinic Receptors via a Pertussis Toxin-insensitive Pathway^*

Moritz Bünemann, Thomas Meyer^§, Lutz Pott^§, and Marlene Hosey^¶

From the  Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611 and the ^§ Institut für Physiologie, Ruhr-Universität, Bochum 44780, Germany

G_i protein-coupled receptors such as the M₂ muscarinic acetylcholine receptor (mAChR) and A₁ adenosine receptor have been shown to activate G protein-activated inwardly rectifying K⁺ channels (GIRKs) via pertussis toxin-sensitive G proteins in atrial myocytes and in many neuronal cells. Here we show that muscarinic M₂ receptors not only activate but also reversibly inhibit these K⁺ currents when stimulated with agonist for up to 2 min. The M₂ mAChR-mediated inhibition of the channel was also observed when the channels were first activated by inclusion of guanosine 5'-O-(thiotriphosphate) in the pipette. Under these conditions the M₂ mAChR-induced inhibition was quasi-irreversible, suggesting a role for G proteins in the inhibitory process. In contrast, when GIRK currents were maximally activated by co-expressing exogenous G, the extent of acetylcholine (ACh)-induced inhibition was significantly reduced, suggesting competition between the receptor-mediated inhibition and the large pool of available G subunits. The signaling pathway that led to the ACh-induced inhibition of GIRK channels was unaffected by pertussis toxin pretreatment. Furthermore, the internalization and agonist-induced phosphorylation of M₂ mAChR was not required because a phosphorylation- and internalization-deficient mutant of the M₂ mAChR was as potent as the wild-type counterpart. Pharmacological agents modulating various protein kinases or phosphatidylinositol 3-kinase did not affect the inhibition of GIRK currents. Furthermore, the signaling pathway that mediates GIRK current inhibition was found to be membrane-delimited because bath application of ACh did not inhibit GIRK channel activity in cell-attached patches. Other G protein-coupled receptors including M₄ mAChR and _1A adrenergic receptors also caused the inhibition, whereas other G protein-coupled receptors including A₁ and A₃ adenosine receptors and _2A and _2C adrenergic receptors could not induce the inhibition. The presented results suggest the existence of a novel signaling pathway that can be activated selectively by M₂ and M₄ mAChR but not by adenosine receptors and that involves non-pertussis toxin-sensitive G proteins leading to an inhibition of G-activated GIRK currents in a membrane-delimited fashion.

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^* This work was funded by National Institutes of Health Grant HL 50121 (to M. H.) and the Deutsche Forschungsgemeinschaft through Research Stipend BU1133/1-1 (to M. B.) and Research Grant PO 212/6-2 (to L. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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.: 312-503-3692; Fax: 312-503-5349; E-mail: mhosey@nwu.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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