Voltage-gated Na+ channelopathies are associated with multiple disorders. Mutations in neuronal Na+ channels cause epilepsy syndromes, ataxia, and autism; mutations in the cardiac Na+ channels are associated with arrhythmias, sudden infant death syndrome, conduction disorders, and cardiomyopathies. A hotspot for disease-causing mutations is the channels' C-terminal domain (CTD), which harbors a calmodulin (CaM) interaction site. Because Ca2+ is the ultimate signal of electrical activity and is often perturbed in disease states, the presence of a key Ca2+ sensor (CaM) at a hotspot for channel regulation (the CTD) provides a starting point for understanding how these channelopathies cause disease. Nevertheless, regulation of Na+ channels by Ca2+/CaM is poorly understood and information is limited by the lack of structural information and challenges to investigating channel function in native cell types. Here, we build on new structural information and novel methods to investigate how Ca2+/CaM regulates Na+ channels in the context of native cell types. Our new structural information provides background and guideposts for investigating how Ca2+-free (apo) CaM and Ca2+-loaded CaM differently affect channel function; how neuronal and cardiac channels are distinctly regulated by CaM in their native cell types, and how different CaM interacting domains within Na+ channels contribute to overall Ca2+/CaM-dependent regulation. Our novel methods of studying informative mutants in cardiomyocytes and neurons will provide an understanding of how Ca2+ affects Na+ channels and thus how Ca2+ dysregulation leads to the various Na+ channelopathies.
The specific Aims addressed in this proposal are to determine: 1) How Ca2+-free apoCaM controls NaV function in neurons and cardiomyocytes; 2) How Ca2+/CaM interaction with the NaV CTD controls NaV function in neurons and cardiomyocytes; and 3) How Ca2+/CaM interaction with the NaV III-IV intracellular linker controls NaV function in neurons and cardiomyocytes.

Public Health Relevance

This grant explores the role of Ca2+/calmodulin-dependent regulation of voltage-gated Na+ channels in physiology and disease, such as in autism, epilepsy, and cardiac arrhythmias, through analysis of the channels' structure and function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Tjurmina, Olga A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
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
Pablo, Juan Lorenzo; Pitt, Geoffrey S (2017) FGF14 is a regulator of KCNQ2/3 channels. Proc Natl Acad Sci U S A 114:154-159
Yan, Haidun; Wang, Chaojian; Marx, Steven O et al. (2017) Calmodulin limits pathogenic Na+ channel persistent current. J Gen Physiol 149:277-293
Pitt, Geoffrey S; Lee, Seok-Yong (2016) Current view on regulation of voltage-gated sodium channels by calcium and auxiliary proteins. Protein Sci 25:1573-84
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
Wan, Elaine; Abrams, Jeffrey; Weinberg, Richard L et al. (2016) Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. J Clin Invest 126:112-22

Showing the most recent 10 out of 15 publications