Regulation of the inward rectifying properties of G-protein-activated inwardly rectifying K+ (GIRK) channels by Gbeta gamma subunits.
Gbetagamma subunits are known to bind to and activate G-protein-activated inwardly rectifying K(+) channels (GIRK) by regulating their open probability and bursting behavior. Studying G-protein regulation of either native GIRK (I(KACh)) channels in feline atrial myocytes or heterologously expressed GIRK1/4 channels in Chinese hamster ovary cells and HEK 293 cells uncovered a novel Gbetagamma subunit mediated regulation of the inwardly rectifying properties of these channels. I(KACh) activated by submaximal concentrations of acetylcholine exhibited a approximately 2.5-fold stronger inward rectification than I(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 Gbetagamma subunits. Analysis of the outward current block underlying inward rectification demonstrated that the fraction of instantaneously blocked channels was reduced when Gbetagamma was over-expressed. The Gbetagamma induced weakening of inward rectification was associated with reduced potencies for Ba(2+) and Cs(+) to block channels from the extracellular side. Based on these results we propose that saturation of the channel with Gbetagamma 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.
Hommers
Leif G
LG
University of Würzburg, Department of Pharmacology & Toxicology, Versbacherstrasse 9, Germany.
Lohse
Martin J
MJ
Bünemann
Moritz
M
D000818:Animals; D016466:CHO Cells; D002415:Cats; D002586:Cesium / Q000494:pharmacology; D006224:Cricetinae; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011487:Protein Conformation
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D002586:Cesium; D020962:Heterotrimeric GTP-Binding Proteins