Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of Kir channels by diverse modulators

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 Mg²⁺ or the βγ-subunits of G proteins. Phosphatidylinositol 4,5-bisphosphate (PIP₂) is an essential factor for maintenance of the activity of all Kir channels. Here, we demonstrate that the strength of channel-PIP₂ interactions determines the sensitivity of Kir channels to regulation by the 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 PIP₂.