MUSCARINIC K- MODAL REGULATION BY G-PROTEIN BETA-GAMMA-SUBUNITS( CHANNEL IN THE HEART )

The membrane-delimited activation of muscarinic K+ channels by G prote in beta gamma subunits plays a prominent role in the inhibitory synapt ic transmission in the heart. These channels are thought to be heterot etramers comprised of two homologous subunits, GIRK1 and CIR, both mem bers of the family of inwardly rectifying K+ channels. Here, we demons trate that muscarinic K+ channels in neonatal rat atrial myocytes exhi bit four distinct gating modes. In intact myocytes, after muscarinic r eceptor activation, the different gating modes were distinguished by d ifferences 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 arc hitecture of the channel, the hypothesis that each of the four gating modes reflects binding of a different number of G beta gamma subunits to the channel was tested, using recombinant G beta(1)gamma(5) G beta( 1)gamma(5) was able to control the equilibrium between the four gating modes of the channel in a manner consistent with binding of G beta ga mma to four equivalent and independent sites in the protein complex. S urprisingly, however, G beta(1)gamma(5) lacked the ability to stabiliz e the long open state of the channel that is responsible for the augme ntation of the mean open time in modes 3 and 4 after muscarinic recept or stimulation. The modal regulation of muscarinic K+ channel gating b y G beta gamma provides the atrial cells with at least two major advan tages: the ability to filter out small inputs from multiple membrane r eceptors and yet the ability to create the gradients of information ne cessary to control the heart rate with great precision.