Activation of the atrial KACh channel by the betagamma subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates.
The betagamma subunits of GTP-binding proteins (Gbetagamma) 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 Gbetagamma 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 with in vitro biochemical studies on the PIP2 requirement for Gbetagamma stimulation of G protein receptor kinase activity, thus implicating phosphatidylinositol phospholipids as a potential control point for Gbetagamma-mediated signal transduction.
Sui
J L
JL
Department of Physiology and Biophysics, Mount Sinai School of Medicine, City University of New York, New York, NY 10029, USA.
Petit-Jacques
J
J
Logothetis
D E
DE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002645:Chickens; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D015640:Ion Channel Gating; D009206:Myocardium / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D014981:Xenopus
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic; D015222:Sodium Channels; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D012964:Sodium; D019204:GTP-Binding Proteins