Structural basis and energy landscape for the Ca(2+) gating and calmodulation of the Kv7.2 K(+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) concentration (10–100 nM), only the N-lobe of CaM is Ca(2+)-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 Ca(2+) levels rise up to 1–10 μM, triggering Ca(2+) 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 Ca(2+)-binding site to the transmembrane region of the channel.