Excitable cell function depends on highly evolved local signaling domains that exert tight spatial and temporal control over post-translational modification (e.g. phosphorylation, oxidation) of ion channels, transporters and receptors. Disruption of these local signaling domains and/or alterations in post-translational modification of membrane proteins are associated with increased susceptibility to arrhythmia in congenital and acquired forms of heart disease, including heart failure. Our research seeks to understand the cellular pathways responsible for local regulation of membrane proteins in specific subcellular domains with the overall objective of generating new insight into human cardiac arrhythmia and sudden death. CaMKII is a multifunctional serine/threonine kinase that regulates a broad spectrum of critical cellular functions in heart. Despite the importance of CaMKII for heart function, little is known regarding the biogenesis of local domains to control CaMKII signaling. We recently demonstrated that the actin-associated polypeptide betaIV-spectrin serves as a novel CaMKII-anchoring protein (CaMKAP), which targets CaMKII to the intercalated disc for regulation of voltage-gated Na+ channel (Nav) function and cardiac excitability. However, the molecular pathway linking betaIV-spectrin/CaMKII to Nav1.5 at the intercalated disc, and mechanisms by which CaMKII alters Nav1.5 function remain unknown. Moreover, the role for CaMKII-dependent regulation of Nav1.5 and cell excitability in heart disease and potentially fatal electrical rhythm disturbances (arrhythmias) is unexplored. Our preliminary data indicate that betaIV-spectrin acts as a scaffold for organizing CaMKII with the adapter protein ankyrin-G and Nav1.5 at the intercalated disc. We have also identified a potential site on Nav1.5 (Ser571) responsible for CaMKII-dependent regulation of Nav function and have developed new reagents to study the role of this site in primary myocytes. Furthermore, we have identified the mechanism for a cluster of human variants adjacent to the CaMKII phosphorylation motif that confer susceptibility to arrhythmia by disrupting normal channel regulation. Finally, our preliminary results indicate that dysregulation of CaMKII-dependent phosphorylation of Nav1.5 occurs in murine and canine models of heart disease, and in failing human hearts. Collectively, these preliminary data support our central hypothesis that betaIV-spectrin organizes a local membrane domain at the cardiomyocyte intercalated disc to control CaMKII-dependent phosphorylation of Nav1.5, and that the CaMKII regulatory motif in Nav1.5 is a critical nodal point for regulating channel function in diverse forms of cardiac disease associated with arrhythmias and sudden death. We expect that targeted disruption of CaMKII/spectrin interaction will prevent CaMKII-dependent phosphorylation of Nav1.5, decrease arrhythmia burden and improve heart function in the setting of myocardial insult. We anticipate that these studies will generate new insight into organization of CaMKII signaling domains, define molecular pathways for regulation of Nav1.5 and cell excitability, and identify novel mechanisms for arrhythmias in both congenital and acquired heart disease.

Public Health Relevance

Cardiac electrical disturbances (arrhythmias) are responsible for most of the 400,000 heart related deaths each year in the United States. At the cellular level, abnormal membrane excitability increases susceptibility to potentially fatal cardiac arrhythmias. These studies will identify molecular pathways for regulation of cell membrane excitability in heart and will generate new insight into mechanisms underlying congenital and common acquired forms of cardiac arrhythmia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Krull, Holly
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Ohio State University
Other Basic Sciences
Schools of Medicine
United States
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Unudurthi, Sathya D; Greer-Short, Amara; Patel, Nehal et al. (2018) Spectrin-based pathways underlying electrical and mechanical dysfunction in cardiac disease. Expert Rev Cardiovasc Ther 16:59-65
Yoo, Shin; Aistrup, Gary; Shiferaw, Yohannes et al. (2018) Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure. JCI Insight 3:
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Onal, Birce; Gratz, Daniel; Hund, Thomas J (2017) Ca2+/calmodulin-dependent kinase II-dependent regulation of atrial myocyte late Na+ current, Ca2+ cycling, and excitability: a mathematical modeling study. Am J Physiol Heart Circ Physiol 313:H1227-H1239
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Unudurthi, Sathya D; Wu, Xiangqiong; Qian, Lan et al. (2016) Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. J Am Heart Assoc 5:e002865
Hund, Thomas J; Mohler, Peter J (2016) Atrial-specific pathways for control of intracellular signaling and myocyte function. J Clin Invest 126:3731-3734

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