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© The Rockefeller University Press, 0022-1295/1997//245/ $5.00
Journal of General Physiology, Volume 109, Number 2, 1997

Article

Effector Contributions to Gβ{gamma}-mediated Signaling as Revealed by Muscarinic Potassium Channel Gating

Tatyana T. Ivanova-Nikolova and Gerda E. Breitwieser

From the Johns Hopkins University School of Medicine, Department of Physiology, Baltimore, Maryland 21205

Receptor-mediated activation of heterotrimeric G proteins leading to dissociation of the G{alpha} subunit from Gβ{gamma} is a highly conserved signaling strategy used by numerous extracellular stimuli. Although Gβ{gamma} subunits regulate a variety of effectors, including kinases, cyclases, phospholipases, and ion channels (Clapham, D.E., and E.J. Neer. 1993. Nature (Lond.). 365:403–406), few tools exist for probing instantaneous Gβ{gamma}-effector interactions, and little is known about the kinetic contributions of effectors to the signaling process. In this study, we used the atrial muscarinic K+ channel, which is activated by direct interactions with Gβ{gamma} subunits (Logothetis, D.E., Y. Kurachi, J. Galper, E.J. Neer, and D.E. Clap. 1987. Nature (Lond.). 325:321–326; Wickman, K., J.A. Iniguez-Liuhi, P.A. Davenport, R. Taussig, G.B. Krapivinsky, M.E. Linder, A.G. Gilman, and D.E. Clapham. 1994. Nature (Lond.). 366: 654–663; Huang, C.-L., P.A. Slesinger, P.J. Casey, Y.N. Jan, and L.Y. Jan. 1995. Neuron. 15:1133–1143), as a sensitive reporter of the dynamics of Gβ{gamma}-effector interactions. Muscarinic K+ channels exhibit bursting behavior upon G protein activation, shifting between three distinct functional modes, characterized by the frequency of channel openings during individual bursts. Acetylcholine concentration (and by inference, the concentration of activated Gβ{gamma}) controls the fraction of time spent in each mode without changing either the burst duration or channel gating within individual modes. The picture which emerges is of a Gβ{gamma} effector with allosteric regulation and an intrinsic "off" switch which serves to limit its own activation. These two features combine to establish exquisite channel sensitivity to changes in Gβ{gamma} concentration, and may be indicative of the factors regulating other Gβ{gamma}-modulated effectors.

Key Words: signal transduction • GTP binding proteins • muscarinic receptor • inward rectifier K+ channel • atrial myocytes

Address correspondence to G.E. Breitwieser, Johns Hopkins University School of Medicine, Department of Physiology, 725 N. Wolfe Street, Baltimore, MD 21205. Fax: 410-955-0461; E-mail: gbreitwi{at}welchlink.welch.jhu.edu

Abbreviations: ACh, acetylcholine


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