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 (G(βγ)) activate the muscarinic K(+) channel (K(ACh)) in heart by direct binding to both of its component subunits. K(ACh) 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 (PIP(2)) mimics the ATP effects and that depletion or block of PIP(2) retards the stimulatory effects of G(βγ) subunits or Na(+) ions on channel activity, effects that can be reversed by restoring PIP(2). Thus, regulation of K(ACh) channel activity may be crucially dependent on PIP(2) and phosphatidylinositol signaling. These striking functional results are in agreement with in vitro biochemical studies on the PIP(2) requirement for G(βγ) stimulation of G protein receptor kinase activity, thus implicating phosphatidylinositol phospholipids as a potential control point for G(βγ)-mediated signal transduction.