Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization

Phosphatidylinositol bisphosphate (PIP2) directly regulates functions as di verse 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 function s. Here, we show in both native cardiac cells and heterologous expression s ystems that receptor-regulated PIP2 hydrolysis results in desensitization o f a GTP-binding protein-stimulated potassium current. Two receptor-regulate d pathways in the plasma membrane cross-talk at the level of these channels to modulate potassium currents. One pathway signals through the beta gamma subunits of G proteins, which bind directly to the channel. G beta gamma s ubunits stabilize interactions with PIP2 and lead to persistent channel act ivation. The second pathway activates phospholipase C (PLC) which hydrolyse s PIP2 and limits G beta gamma-stimulated activity. Our results provide evi dence that PIP2 itself is a receptor-regulated second messenger, downregula tion of which accounts for a new form of desensitization.