Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K super(+) (GIRK) Channels by G[beta][gamma] Subunits

G[beta][gamma] subunits are known to bind to and activate G-protein-activated inwardly rectifying K super(+) channels (GIRK) by regulating their open probability and bursting behavior. Studying G-protein regulation of either native GIRK (I sub(KACh)) channels in feline atrial myocytes or heterologously expressed GIRK1/4 channels in Chinese hamster ovary cells and HEK 293 cells uncovered a novel G[beta][gamma] subunit mediated regulation of the inwardly rectifying properties of these channels. I sub(KACh) activated by submaximal concentrations of acetylcholine exhibited a 2.5-fold stronger inward rectification than I sub(KACh) activated by saturating concentrations of acetylcholine. Similarly, the inward rectification of currents through GIRK1/4 channels expressed in HEK cells was substantially weakened upon maximal stimulation with co-expressed G[beta][gamma] subunits. Analysis of the outward current block underlying inward rectification demonstrated that the fraction of instantaneously blocked channels was reduced when G[beta][gamma] was over-expressed. The G[beta][gamma] induced weakening of inward rectification was associated with reduced potencies for Ba super(2+) and Cs super(+) to block channels from the extracellular side. Based on these results we propose that saturation of the channel with G[beta][gamma] leads to a conformational change within the pore of the channel that reduced the potency of extracellular cations to block the pore and increased the fraction of channels inert to a pore block in outward direction.