Pharmacological augmentation of neuronal potassium currents by small molecule drugs is now an attractive strategy to treat certain hyperexcitatory neurological diseases including epilepsies. The combination of homologous subunits and distinct functional roles of various potassium channels argues for subtype selectivity of active small molecules. Compound selectivity for a targeted protein is commonly attributed to biochemical binding specificity.

Researchers from the International Scientist Working Station of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM), revealed that the drug selectivity on protein targets is dynamic and may be regulated by receptor signaling via PIP2.

Zinc pyrithione (ZnPy) is a potent activator for KCNQ channels with selectivity for KCNQ1, 2, 4 and 5, but not homologous KCNQ3 potassium channel. However, this study shows that KCNQ3 in fact possesses a ZnPy binding site and ZnPy effectively augments KCNQ3 once phosphatidylinositol 4,5-bisphosphate (PIP2) is reduced by a receptor signaling pathway. The potency (EC50) of ZnPy remains the same under different PIP2 concentrations, indicating that PIP2 does not directly regulate the binding affinity of ZnPy.

In cultured neurons with a reduced PIP2 level caused by activated muscarinic signaling, the retigabine becomes ineffective in dampening the spontaneous firing. In contrast, ZnPy remains efficacious. The dynamic shift of pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a new PIP2 site within the S4-S5 linker of KCNQ3. These results provide evidence that subtype selectivity is preconditioned and may be regulated by an intracellular second messenger.

This study entitled “PIP2 alters pharmacological selectivity for epilepsy-causing KCNQ channels” was released in the Proceedings of the National Academy of Sciences.