Structural basis and energy landscape for the Ca²⁺ gating and calmodulation of the Kv7.2 K⁺ channel.

Abstract

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 <i>h</i>A and <i>h</i>B 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.