The study elucidates the structural mechanism by which calcium binding to calmodulin allosterically regulates the gating of the Kv7.2 potassium channel.
The Kv7.2 (KCNQ2) channel is the principal molecular component of the slow voltage-gated, noninactivating K⁺ M-current, a key controller of neuronal excitability. To investigate the calmodulin (CaM)-mediated Ca²⁺ gating of the channel, we used NMR spectroscopy to structurally and dynamically describe the association of helices hA and hB of Kv7.2 with CaM, as a function of Ca²⁺ concentration. The structures of the CaM/Kv7.2-hAB complex at two different calcification states are reported here. In the presence of a basal cytosolic Ca²⁺ concentration (10-100 nM), only the N-lobe of CaM is Ca²⁺-loaded and the complex (representative of the open channel) exhibits collective dynamics on the millisecond time scale toward a low-populated excited state (1.5%) that corresponds to the inactive state of the channel. In response to a chemical or electrical signal, intracellular Ca²⁺ levels rise up to 1-10 μM, triggering Ca²⁺ association with the C-lobe. The associated conformational rearrangement is the key biological signal that shifts populations to the closed/inactive channel. This reorientation affects the C-lobe of CaM and both helices in Kv7.2, allosterically transducing the information from the Ca²⁺-binding site to the transmembrane region of the channel.
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Bernardo‐Seisdedos et al. (2018) studied this question.
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