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

TLDR

Cardiac Na⁺/Ca²⁺ exchange is ATP‑dependent but not protein‑kinase mediated. ATP converts PI to PIP₂ in cardiac membranes, a conversion inhibited by PI‑specific PLC, reversed by PIP₂‑specific PLC, mimicked by exogenous PIP₂, accelerated by high Ca²⁺, blocked by aluminum binding PIP₂, and selectively regulates ATP‑inhibited K_ATP channels but not Na⁺/K⁺ pumps or Na⁺ channels, indicating PIP₂ as a key regulator of cardiac ion transporters and channels.

Abstract

Cardiac Na + ,Ca 2+ 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 (PIP 2 ) 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 PIP 2 -specific PLC; and it was mimicked by exogenous PIP 2 . High concentrations of free Ca 2+ (5 to 20 μM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca 2+ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP 2 . ATP-inhibited potassium channels (K ATP ) were also sensitive to PIP 2 , whereas Na + ,K + pumps and Na + channels were not. Thus, PIP 2 may be an important regulator of both ion transporters and channels.