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A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel.

Johnson CN, Potet F, Thompson MK, Kroncke BM, Glazer AM, Voehler MW, Knollmann BC, George AL, Chazin WJ
Structure. 2018 26 (5): 683-694.e3

PMID: 29606593 · PMCID: PMC5932218 · DOI:10.1016/j.str.2018.03.005

The function of the human cardiac sodium channel (Na1.5) is modulated by the Ca sensor calmodulin (CaM), but the underlying mechanism(s) are controversial and poorly defined. CaM has been reported to bind in a Ca-dependent manner to two sites in the intracellular loop that is critical for inactivation of Na1.5 (inactivation gate [IG]). The affinity of CaM for the complete IG was significantly stronger than that of fragments that lacked both complete binding sites. Structural analysis by nuclear magnetic resonance, crystallographic, and scattering approaches revealed that CaM simultaneously engages both IG sites using an extended configuration. Patch-clamp recordings for wild-type and mutant channels with an impaired CaM-IG interaction revealed CaM binding to the IG promotes recovery from inactivation while impeding the kinetics of inactivation. Models of full-length Na1.5 suggest that CaM binding to the IG directly modulates channel function by destabilizing the inactivated state, which would promote resetting of the IG after channels close.

Copyright © 2018 Elsevier Ltd. All rights reserved.

MeSH Terms (11)

Binding Sites Calcium Calmodulin Crystallography, X-Ray Gene Expression Regulation Humans Kinetics Models, Molecular Mutation NAV1.5 Voltage-Gated Sodium Channel Protein Binding

Connections (3)

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