Activation of the atrial K ACh channel by the βγ subunits of G proteins or intracellular Na + ions depends on the presence of phosphatidylinositol phosphates

The βγ subunits of GTP-binding proteins (Gβγ ) activate the muscarinic K+ channel (KACh ) in heart by direct binding to both of its component subunits. KACh channels can also be gated by internal Na+ ions. Both activation mechanisms show dependence on hydrolysis of intracellular ATP. We report that phosphatidylinositol 4,5-bisphosphate (PIP2 ) mimics the ATP effects and that depletion or block of PIP2 retards the stimulatory effects of Gβγ subunits or Na+ ions on channel activity, effects that can be reversed by restoring PIP2 . Thus, regulation of KACh channel activity may be crucially dependent on PIP2 and phosphatidylinositol signaling. These striking functional results are in agreement within vitro biochemical studies on the PIP2 requirement for Gβγ stimulation of G protein receptor kinase activity, thus implicating phosphatidylinositol phospholipids as a potential control point for Gβγ -mediated signal transduction.