Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. While all five potassium channel subtypes (KCNQ1-KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione. Retigabine is more effective on KCNQ3 than KCNQ2, whereas zinc pyrithione is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not zinc pyrithione. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) causes KCNQ3 to become sensitive to zinc pyrithione but lose sensitivity to retigabine. 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. Further investigations in KCNQ2 revealed that, in the closed state, PIP2 is anchored at the S2-S3 loop; upon channel activation, PIP2 interacts with the S4-S5 linker and is involved in channel gating. Therefore, our results provide new insights into the action mechanism of PIP2 on KCNQ channels and support the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP2.