Molecular overlap in the regulation of SK channels by small molecules and phosphoinositides

Phosphatidylinositol 4,5-bisphosphate (PIP(2)) directly interacts with the small-conductance Ca(2+)-activated K(+) 2-a (SK2-a) channel/calmodulin complex, serving as a critical element in the regulation of channel activity. We report that changes of protein conformation in close proximity to the PIP(2) binding site induced by a small-molecule SK channel modulator, NS309, can effectively enhance the interaction between the protein and PIP(2) to potentiate channel activity. This novel modulation of PIP(2) sensitivity by small-molecule drugs is likely not to be limited in its application to SK channels, representing an intriguing strategy to develop drugs controlling the activity of the large number of PIP(2)-dependent proteins.