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J Cell Sci. 2015 Nov 1;128(21):4014-23. doi: 10.1242/jcs.176420. Epub 2015 Sep 10.

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation.

Author information

1
Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
2
Departament de Farmacología, UPV/EHU, Universidad del País Vasco, Barrio Sarriena s/n, Leioa 48940, Spain.
3
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, München 81377, Germany.
4
Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain alvaro.villarroel@csic.es.

Abstract

We show that the combination of an intracellular bi-partite calmodulin (CaM)-binding site and a distant assembly region affect how an ion channel is regulated by a membrane lipid. Our data reveal that regulation by phosphatidylinositol(4,5)bisphosphate (PIP2) and stabilization of assembled Kv7.2 subunits by intracellular coiled-coil regions far from the membrane are coupled molecular processes. Live-cell fluorescence energy transfer measurements and direct binding studies indicate that remote coiled-coil formation creates conditions for different CaM interaction modes, each conferring different PIP2 dependency to Kv7.2 channels. Disruption of coiled-coil formation by epilepsy-causing mutation decreases apparent CaM-binding affinity and interrupts CaM influence on PIP2 sensitivity.

KEYWORDS:

Allosteric; Calmodulin; Coiled-coil; Epilepsy; KCNQ; Leucine zipper; M-current; PIP2

PMID:
26359296
DOI:
10.1242/jcs.176420
[Indexed for MEDLINE]
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