Voltage-gated Na channels (NaV) initiate electrical impulses in neurons and the heart. Mutations in SCN1A and SCN2A, which encode the neuronal channels NaV1.1 and NaV1.2, respectively, cause inherited epilepsy syndromes. Mutations in SCN5A, which encodes the major subtype of NaV channel in heart (NaV1.5), are linked to many cardiac arrhythmogenic disorders, such as Long QT syndrome (LQTS) and Brugada syndrome (BrS). The main structural components of NaV channels are four homologous repeats, which assemble in a tetrameric configuration within the membrane to control voltage-dependent Na+ conduction, and a cytosolic C-terminal domain (CTD) that serves as a binding site for many auxiliary regulatory proteins and is a hotspot for disease-causing mutations. Among these auxiliary CTD-interacting proteins, the ubiquitous Ca2+ sensor calmodulin (CaM) and fibroblast growth factor homologous factors (FHFs;FGF11-FGF14) are of particular interest: many disease- causing mutations are localized to their putative interaction domains within the CTDs of specific NaV channels;FGF14 is itself a locus for the neurodegenerative disorder spinocerebellar ataxia 27;and Ca2+ regulation of NaV channels by CaM is poorly understood. A lack of structural information for these interactions with the CTD, however, has prevented an understanding of the roles of the CTDs, these auxiliary proteins in channel regulation, and the molecular basis of mutational effects on NaV that lead to disease. Building on recent success in determining the crystal structure of a NaV CTD in complex with CaM and an FHF;and in defining new roles for FHFs in regulation of NaV channel gating and trafficking, we propose to define the mechanisms of NaV channel regulation by Ca2+/CaM, and FHFs and to uncover the molecular basis of the mutational effects on NaV CTDs and their associated proteins that lead to channelopathies. To achieve these goals, we propose the following specific aims: 1. Structure-function studies to determine how Ca2+/CaM regulate NaV channel function, using electrophysiology and biochemistry, to probe insights gained from structural determination;2. Structure-function studies to determine how FHFs regulate NaV channel function and how FHFs co-operate with CaM for channel regulation;3. Physiological investigations of the consequences of FHF regulation of NaV1.5. Because NaV channelopathies and mutations in FHFs are associated with neurodegenerative diseases, epilepsy syndromes, and cardiac arrhythmias, the proposed project has great potential to illuminate the molecular basis of multiple channelopathies in multiple organ systems due to NaV CTD mutations and, more generally, to uncover fundamental aspects of NaV channel structure-function.

Public Health Relevance

This grant explores the role of voltage-gated Na+ channels in physiology and disease, such as in cardiac arrhythmias, through analysis of the channels'structure and the structure of associated subunits.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Krull, Holly
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Wei, Eric Q; Sinden, Daniel S; Mao, Lan et al. (2017) Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload. Proc Natl Acad Sci U S A 114:E4010-E4019
Wang, Xiangchong; Tang, He; Wei, Eric Q et al. (2017) Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles. J Mol Cell Cardiol 104:63-74
Pablo, Juan Lorenzo; Pitt, Geoffrey S (2017) Divide, multitask, and conquer: Coordination in channel regulation. Channels (Austin) 11:268-270
Yan, Haidun; Wang, Chaojian; Marx, Steven O et al. (2017) Calmodulin limits pathogenic Na+ channel persistent current. J Gen Physiol 149:277-293
Choi, Jong-Il; Wang, Chaojian; Thomas, Matthew J et al. (2016) ?1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current. PLoS One 11:e0152355
Wang, Hong-Gang; Zhu, Wandi; Kanter, Ronald J et al. (2016) A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias. J Mol Cell Cardiol 92:52-62
Pablo, Juan L; Pitt, Geoffrey S (2016) Fibroblast Growth Factor Homologous Factors: New Roles in Neuronal Health and Disease. Neuroscientist 22:19-25
Yang, Jing; Wang, Zhihua; Sinden, Daniel S et al. (2016) FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner. Channels (Austin) 10:410-420
Matsui, Maiko; Pitt, Geoffrey S (2016) Genetic variants and disease: correlate or cause? Eur Heart J 37:1476-8
Pablo, Juan Lorenzo; Wang, Chaojian; Presby, Matthew M et al. (2016) Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action. Proc Natl Acad Sci U S A 113:E2665-74

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