Figure 2. Modified concurrent dual mode of KCNQ channel inhibition .

In this model, phosphorylation of KCNQ channels functions to reduce their PIP₂ affinity, priming them to small changes in PIP₂ abundance induced by physiological stimulation of receptors. A, activation of receptors that are part of AKAP79150–KCNQ complexes rapidly depletes PIP₂ and activates AKAP79/150‐anchored PKC, which phosphorylates KCNQ subunits near the CaM binding site on the B helix, altering the configuration of CaM and KCNQ channels. KCNQ channels thus sense both PIP₂ depletion and phosphorylation‐mediated PIP₂‐affinity reduction. B, activation of receptors located close to IP₃ receptors, but outside of the AKAP–KCNQ complexes, induces intracellular Ca²⁺ rises and Ca²⁺ binding to CaM, which undergoes a conformational change on the overlapping binding sites with AKAP150 on the carboxy‐terminus of KCNQ channels. This induces a lowered interaction between KCNQ and AKAP79/150, thus preventing PKC phosphorylation.