Abstract
Phosphatidylinositol bisphosphate (PIP2) directly regulates functions as diverse as the organization of the cytoskeleton, vesicular transport and ion channel activity. It is not known, however, whether dynamic changes in PIP2 levels have a regulatory role of physiological importance in such functions. Here, we show in both native cardiac cells and heterologous expression systems that receptor-regulated PIP2 hydrolysis results in desensitization of a GTP-binding protein-stimulated potassium current. Two receptor-regulated pathways in the plasma membrane cross-talk at the level of these channels to modulate potassium currents. One pathway signals through the betagamma subunits of G proteins, which bind directly to the channel. Gbetagamma subunits stabilize interactions with PIP2 and lead to persistent channel activation. The second pathway activates phospholipase C (PLC) which hydrolyses PIP2 and limits Gbetagamma-stimulated activity. Our results provide evidence that PIP2 itself is a receptor-regulated second messenger, downregulation of which accounts for a new form of desensitization.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Acetylcholine / pharmacology
-
Animals
-
Animals, Newborn
-
COS Cells
-
Cell Membrane / drug effects
-
Cell Membrane / enzymology
-
Cell Membrane / metabolism*
-
Cells, Cultured
-
Electric Conductivity
-
Enzyme Activation / drug effects
-
ErbB Receptors / chemistry
-
ErbB Receptors / metabolism
-
Estrenes / pharmacology
-
G Protein-Coupled Inwardly-Rectifying Potassium Channels
-
Heart Atria / cytology
-
Heart Atria / drug effects
-
Heart Atria / enzymology
-
Heart Atria / metabolism
-
Heterotrimeric GTP-Binding Proteins / metabolism
-
Hydrolysis / drug effects
-
Ion Channel Gating* / drug effects
-
Oocytes / metabolism
-
Phosphatidylinositol 4,5-Diphosphate / metabolism*
-
Potassium / metabolism*
-
Potassium Channel Blockers
-
Potassium Channels / metabolism
-
Potassium Channels, Inwardly Rectifying*
-
Pyrrolidinones / pharmacology
-
Rats
-
Receptor Cross-Talk / drug effects
-
Receptor, Muscarinic M1
-
Receptor, Muscarinic M2
-
Receptors, Cell Surface / agonists
-
Receptors, Cell Surface / chemistry
-
Receptors, Cell Surface / metabolism*
-
Receptors, Muscarinic / chemistry
-
Receptors, Muscarinic / metabolism
-
Second Messenger Systems* / drug effects
-
Type C Phospholipases / antagonists & inhibitors
-
Type C Phospholipases / metabolism
-
Xenopus laevis
Substances
-
Estrenes
-
G Protein-Coupled Inwardly-Rectifying Potassium Channels
-
Phosphatidylinositol 4,5-Diphosphate
-
Potassium Channel Blockers
-
Potassium Channels
-
Potassium Channels, Inwardly Rectifying
-
Pyrrolidinones
-
Receptor, Muscarinic M1
-
Receptor, Muscarinic M2
-
Receptors, Cell Surface
-
Receptors, Muscarinic
-
1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
-
ErbB Receptors
-
Type C Phospholipases
-
Heterotrimeric GTP-Binding Proteins
-
Acetylcholine
-
Potassium