Effector contributions to G beta gamma-mediated signaling as revealed by muscarinic potassium channel gating.
Receptor-mediated activation of heterotrimeric G proteins leading to dissociation of the G alpha subunit from G beta gamma is a highly conserved signaling strategy used by numerous extracellular stimuli. Although G beta 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 G beta 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 G beta 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 G beta 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 G beta 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 G beta 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 G beta gamma concentration, and may be indicative of the factors regulating other G beta gamma-modulated effectors.
Ivanova-Nikolova
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Johns Hopkins University School of Medicine, Department of Physiology, Baltimore, Maryland 21205, USA.
Breitwieser
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D000818:Animals; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011892:Rana catesbeiana; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D015221:Potassium Channels; D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins