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Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2395-2400. doi: 10.1073/pnas.1800235115. Epub 2018 Feb 20.

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

Author information

1
Protein Stability and Inherited Disease Laboratory, Center for Cooperative Research in Biosciences CIC bioGUNE, 48170 Derio, Spain.
2
Instituto Biofisika (Consejo Superior de Investigaciones Científicas, Universidad del País Vasco), University of Basque Country, 48940 Leioa, Spain.
3
Instituto Biofisika (Consejo Superior de Investigaciones Científicas, Universidad del País Vasco), University of Basque Country, 48940 Leioa, Spain alvaro.villarroel@csic.es omillet@cicbiogune.es.
4
Protein Stability and Inherited Disease Laboratory, Center for Cooperative Research in Biosciences CIC bioGUNE, 48170 Derio, Spain; alvaro.villarroel@csic.es omillet@cicbiogune.es.

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 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.

KEYWORDS:

Kv7 potassium channel; M-current; calcium regulation; calmodulin; ion channel

PMID:
29463698
PMCID:
PMC5873240
DOI:
10.1073/pnas.1800235115
[Indexed for MEDLINE]
Free PMC Article

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