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Updated: Feb 12, 2026

Pull-down of Calmodulin-binding Proteins
Published on: January 23, 2012
A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel
Christopher N Johnson1, Franck Potet2, Matthew K Thompson3
1Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37240, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37205, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Arrhythmia Research and Therapeutics, Vanderbilt University, Nashville, TN 37240, USA.
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.
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