Calcium‐induced structural changes of the CaM–KCNQ complex

Abstract

Association with ubiquitous calcium‐binding protein calmodulin (CaM) endows KCNQ (Kv7) potassium channels with sensitivity to intracellular calcium levels. While it is generally known that CaM binds to the cytoplasmic C‐termini of these channels, conformational changes underlying CaM‐dependent KCNQ modulation remain poorly understood. Previously, we used an intracellular tethered blocker approach in a combination with whole cell recordings to generate a quaternary structural model of CaM bound to a functioning KCNQ2/KCNQ3 channel. This structure positions CaM adjacent to the KCNQ activation gate. Here, we tested the hypothesis that calcium binding induces a repositioning of the CaM lobes bound to the channels. Comparison of the radial distances for fully calcified CaM to two different mutants that prevent calcium binding to either N‐ or C‐lobe (CaM1–2 or CaM3–4, respectively) demonstrated significant conformational changes in KCNQ/CaM1–2 (but not CaM3–4) complexes. These findings support the notion that calcification of the N‐lobe of Ca‐M results in conformational changes in CaMKCNQ complex, which underlie its sensitivity to intracellular calcium.