State-dependent modification of ATP-sensitive K+ channels by phosphatidylinositol 4,5-bisphosphate

With inside-out patchrecordings in ventricular myocytes from the hearts of guinea pigs, westudied ATP-sensitive K⁺ (K_ATP) channelsactivated by phosphatidylinositol 4,5-bisphosphate (PIP₂)with respect to sensitivity to ATP when in either a rundown state (RS)or a non-rundown state (NRS). Rundown of K_ATP channels wasinduced by exposure either to ATP-free solution or to ATP-free solutioncontaining 19 µM Ca²⁺. Exposure of membrane patches to 10 µM PIP₂ reactivated channels with both types of rundown.The reactivation by PIP₂ did not require ATP in the bath.The IC₅₀ of channels recovered from RS and before therundown was 37.1 and 31.1 µM, respectively. PIP₂irreversibly increased the mean current when the channel was in theNRS. This was associated with a shift of IC₅₀ to 250.6 µMafter PIP₂ exposure. PIP₂ activates NRSK_ATP channels by decreasing their sensitivity to ATP,whereas PIP₂ reactivates RS-K_ATP channelsindependently of ATP without changing ATP sensitivity.