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

With inside-out patch recordings in ventricular myocytes from the hearts of guinea pigs, we studied ATP-sensitive K+ (K-ATP) channels activated by pho sphatidylinositol 4,5-bisphosphate (PIP2) with respect to sensitivity to AT P when in either a rundown state (RS) or a non-rundown state (NRS). Rundown of K-ATP channels was induced by exposure either to ATP-free solution or t o ATP-free solution containing 19 muM Ca2+. Exposure of membrane patches to 10 muM PIP2 reactivated channels with both types of rundown. The reactivat ion by PIP2 did not require ATP in the bath. The IC50 of channels recovered from RS and before the rundown was 37.1 and 31.1 muM, respectively. PIP2 i rreversibly increased the mean current when the channel was in the NRS. Thi s was associated with a shift of IC50 to 250.6 muM after PIP2 exposure. PIP 2 activates NRS KATP channels by decreasing their sensitivity to ATP, where as PIP2 reactivates RS-K-ATP channels independently of ATP without changing ATP sensitivity.