A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel

Christopher N. Johnson*, Franck Potet, Matthew K. Thompson, Brett M. Kroncke, Andrew M. Glazer, Markus W. Voehler, Bjorn C. Knollmann, Alfred L. George, Walter J. Chazin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

The function of the human cardiac sodium channel (NaV1.5) is modulated by the Ca2+ sensor calmodulin (CaM), but the underlying mechanism(s) are controversial and poorly defined. CaM has been reported to bind in a Ca2+-dependent manner to two sites in the intracellular loop that is critical for inactivation of NaV1.5 (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 NaV1.5 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. The mechanism of calcium regulation of cardiac sodium channel (NaV1.5) gating is much debated. Johnson et al. define a strong, calcium-dependent interaction between the intracellular calcium sensor calmodulin and the gate controlling inactivation of NaV1.5. They find that calmodulin binding to the gate alters the recovery from inactivation.

Original languageEnglish (US)
Pages (from-to)683-694.e3
JournalStructure
Volume26
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • X-ray crystallography
  • calcium regulation
  • cardiac sodium channel (NaV1.5)
  • small angle X-ray scattering (SAXS)
  • solution NMR spectroscopy
  • structural biology
  • whole-cell patch-clamp electrophysiology

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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