ACTIVATION OF THE ATRIAL K-ACH CHANNEL BY THE BETA-GAMMA-SUBUNITS OF G-PROTEINS OR INTRACELLULAR NA+ IONS DEPENDS ON THE PRESENCE OF PHOSPHATIDYLINOSITOL PHOSPHATES

The beta gamma subunits of GTP-binding proteins (G(beta gamma)) activa te the muscarinic K+ channel (K-ACh) in heart by direct binding to bot h of its component subunits. K-ACh channels can also be gated by inter nal Na+ ions. Both activation mechanisms show dependence on hydrolysis of intracellular ATP. We report that phosphatidylinositol 4,5-bisphos phate (PIP2) mimics the ATP effects and that depletion or block of PIP 2 retards the stimulatory effects of G(beta gamma) subunits or Na+ ion s on channel activity, effects that can be reversed by restoring PIP2. Thus, regulation of K-ACh channel activity may be crucially dependent on PIP2 and phosphatidylinositol signaling. These striking functional results are in agreement with in vitro biochemical studies on the PIP 2 requirement for G(beta gamma) stimulation of G protein receptor kina se activity, thus implicating phosphatidylinositol phospholipids as a potential control point for G(beta gamma)-mediated signal transduction .