Regulation of Cardiac Na + ,Ca 2+ Exchange and K ATP Potassium Channels by PIP 2

Abstract

Cardiac Na⁺,Ca²⁺ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate (ATP) but is not mediated by protein kinases. In giant cardiac membrane patches, ATP acted to generate phosphatidylinositol-4,5-bisphosphate (PIP₂) from phosphatidylinositol (PI). The action of ATP was abolished by a PI-specific phospholipase C (PLC) and recovered after addition of exogenous PI; it was reversed by a PIP₂-specific PLC; and it was mimicked by exogenous PIP₂. High concentrations of free Ca²⁺ (5 to 20 μM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca²⁺ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP₂. ATP-inhibited potassium channels (K_ATP) were also sensitive to PIP₂, whereas Na⁺,K⁺ pumps and Na⁺ channels were not. Thus, PIP₂ may be an important regulator of both ion transporters and channels.