The activity of specific inwardly rectifying potassium (Kir) channels is regulated by any of a number of different modulators, such as protein kinase C, G q -coupled receptor stimulation, pH, intracellular Mg 2؉ or the ␤␥subunits of G proteins. Phosphatidylinositol 4,5bisphosphate (PIP 2 ) is an essential factor for maintenance of the activity of all Kir channels. Here, we demonstrate that the strength of channel-PIP 2 interactions determines the sensitivity of Kir channels to regulation by the

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... various modulators. Furthermore, our results suggest that differences among Kir channels in their specific regulation by a given modulator may reflect differences in their apparent affinity of interactions with PIP 2 .