Atrial fibrillation is the most common arrhythmia in man and confers a significant morbidity and increased risk of mortality. Gap junction channels are likely to play significant roles in the stabilization and maintenance of atrial fibrillation, since atrial fibrillation is associated with remodeling of connections between atrial myocytes and altered electrical conduction. These channels (made of connexin subunits, CX) provide a pathway for direct intercellular passage of ions and small molecules facilitating cardiac electrical conduction and coordination of the responses of cardiovascular cells to intracellular signals. Two major connexins (CX40 and CX43) are expressed in the atrium. A variety of provocative studies suggest that alterations of CX40 (including reduced levels, heterogeneity of distribution, and mutations) contribute to the pathogenesis of atrial fibrillation. A series of experiments are proposed: (1) to test the hypothesis that alterations of CX40 alone or relative to CX43 are present in atrial tissue from patients with atrial fibrillation, and (2) to use expression systems to test how these alterations can affect intercellular communication. The results of the proposed experiments will clarify the role of gap junctions in cardiac arrhythmias. They will also elucidate the basic cellular biology and physiology of gap junction-mediated intercellular communication.

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The normal functioning of the heart depends on passage of electrical current between cells and is facilitated by intercellular channels contained within structures known as gap junctions. Disturbances of electrical conduction lead to abnormal heart rhythms such as atrial fibrillation. Our studies will clarify how abnormalities of the subunit gap junction proteins lead to arrhythmias such as atrial fibrillation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-CVRS-F (03))
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Przywara, Dennis
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University of Chicago
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Gemel, Joanna; Su, Zihan; Gileles-Hillel, Alex et al. (2017) Intermittent hypoxia causes NOX2-dependent remodeling of atrial connexins. BMC Cell Biol 18:7
Beyer, Eric C (2015) Are these connexins compatible and does it matter? Channels (Austin) 9:63-4
Gemel, Joanna; Simon, Adria R; Patel, Dakshesh et al. (2014) Degradation of a connexin40 mutant linked to atrial fibrillation is accelerated. J Mol Cell Cardiol 74:330-9
Rutledge, Cody A; Ng, Fu Siong; Sulkin, Matthew S et al. (2014) c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. J Am Coll Cardiol 63:928-34
Gemel, Joanna; Levy, Andrew E; Simon, Adria R et al. (2014) Connexin40 abnormalities and atrial fibrillation in the human heart. J Mol Cell Cardiol 76:159-68
Patel, Dakshesh; Gemel, Joanna; Xu, Qin et al. (2014) Atrial fibrillation-associated connexin40 mutants make hemichannels and synergistically form gap junction channels with novel properties. FEBS Lett 588:1458-64
O'Donnell 3rd, James J; Birukova, Anna A; Beyer, Eric C et al. (2014) Gap junction protein connexin43 exacerbates lung vascular permeability. PLoS One 9:e100931
Yan, Jiajie; Kong, Wei; Zhang, Qiang et al. (2013) c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias. Cardiovasc Res 97:589-97
Beyer, Eric C; Lin, Xianming; Veenstra, Richard D (2013) Interfering amino terminal peptides and functional implications for heteromeric gap junction formation. Front Pharmacol 4:67
Smith, Tekla D; Mohankumar, Aditi; Minogue, Peter J et al. (2012) Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization. J Membr Biol 245:221-30

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