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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL122967-03
Application #
9407103
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Lathrop, David A
Project Start
2014-11-15
Project End
2018-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
$541,014
Indirect Cost
$114,343
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
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
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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