J. Gen. Physiol., Volume 112, Number 2, August 1, 1998 199-210

Muscarinic K⁺ Channel in the Heart
Modal Regulation by G Protein Subunits

Tatyana T. Ivanova-Nikolova, Emil N. Nikolov, Carl Hansen, and Janet D. Robishaw

From the Henry Hood MD Research Program, Department of Cellular and Molecular Physiology, Penn State College of Medicine, Danville, Pennsylvania 17822

The membrane-delimited activation of muscarinic K⁺ channels by G protein subunits plays a prominent role in the inhibitory synaptic transmission in the heart. These channels are thought to be heterotetramers comprised of two homologous subunits, GIRK1 and CIR, both members of the family of inwardly rectifying K⁺ channels. Here, we demonstrate that muscarinic K⁺ channels in neonatal rat atrial myocytes exhibit four distinct gating modes. In intact myocytes, after muscarinic receptor activation, the different gating modes were distinguished by differences in both the frequency of channel opening and the mean open time of the channel, which accounted for a 76-fold increase in channel open probability from mode 1 to mode 4. Because of the tetrameric architecture of the channel, the hypothesis that each of the four gating modes reflects binding of a different number of G subunits to the channel was tested, using recombinant G₁₅. G₁₅ was able to control the equilibrium between the four gating modes of the channel in a manner consistent with binding of G to four equivalent and independent sites in the protein complex. Surprisingly, however, G₁₅ lacked the ability to stabilize the long open state of the channel that is responsible for the augmentation of the mean open time in modes 3 and 4 after muscarinic receptor stimulation. The modal regulation of muscarinic K⁺ channel gating by G provides the atrial cells with at least two major advantages: the ability to filter out small inputs from multiple membrane receptors and yet the ability to create the gradients of information necessary to control the heart rate with great precision.

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