The ICl,swell inhibitor DCPIB blocks Kir channels that possess weak affinity for PIP2

Inwardly rectifying K + (Kir) channels are important contributors to the resting membrane potential and regulate cellular excitability. The activity of Kir channels depends critically on the phospholipid PIP 2 . Several modulators of the activity of Kir channels alter the apparent affinity of the channel to PIP 2 . Channels with high apparent affinity to PIP 2 may not respond to a given modulator, but mutations that decrease such affinity can render the channel susceptible to modulation. Here, we identify a known inhibitor of the swelling-activated Cl − current, DCPIB, as an effective inhibitor of a number of Kir channels both in native cardiac cells and in heterologous expression systems. We show that the apparent affinity to PIP 2 determines whether DCPIB will serve as an efficient blocker of Kir channels. These effects are consistent with a model in which DCPIB competes with PIP 2 for a common binding site.