Muscarinic K+ channel in the heart. Modal regulation by G protein beta gamma subunits

The membrane-delimited activation of muscarinic K+ channels by G protein beta gamma 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 Gbeta gamma subunits to the channel was tested, using recombinant Gbeta1 gamma5. Gbeta1 gamma5 was able to control the equilibrium between the four gating modes of the channel in a manner consistent with binding of Gbeta gamma to four equivalent and independent sites in the protein complex. Surprisingly, however, Gbeta1 gamma5 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 Gbeta gamma 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.