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-mediated Signaling as Revealed
by Muscarinic Potassium Channel Gating
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
subunit
from G
is a highly conserved signaling strategy used by numerous extracellular stimuli. Although G 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-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 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-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) 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 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 concentration, and may be indicative of the factors regulating other G-modulated effectors.
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