Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Junctional complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Also resident to the intercalated disc are molecules not traditionally considered "junctional," that is, not involved in providing a physical continuum between neighboring cells. Here, we seek a better understanding of the association between mechanical junctions, gap junctions and the voltage-gated sodium channel (VGSC) complex. Experiments stem from our observations that loss of expression of the desmosomal protein plakophilin-2 (PKP2) leads to a decrease in amplitude and a shift in kinetics of the sodium current. Our preliminary data further indicate that the cytoskeletal adaptor protein ankyrin-G (ankG), which is known to associate with the cardiac sodium channel protein, functionally interacts with PKP2 and with the gap junction protein connexin43 (Cx43). Thus, we test the overall hypothesis that there is a functional interdependence of the mechanical junctions with the voltage-gated sodium channel complex, and that molecules within both components can influence gap junction mediated intercellular communication in the heart. Specifics Aims are: 1: To characterize the interaction of ankyrin-G with the gap junction protein connexin43. 2: To study the reciprocal interaction of ankyrin-G with proteins involved in mechanical coupling between cells. 3: To assess the dependence of the sodium current on the expression of desmosomal proteins. We speculate that this "other" electromechanical coupling, occurring at the intercalated disc, may be relevant not only in the understanding of arrhythmogenesis in rare inherited diseases, but also in acquired conditions (cardiomyopathies) affecting the integrity of the intercalated disc.

Public Health Relevance

Intercellular communication is essential for proper cardiac function. Cells in the heart interact with each other both mechanically and electrically. Here we will study how changes in molecules important for mechanical function, also affect electrical behavior. These studies may help in the understanding of why patients with diseases of the heart muscle, sometimes suffer severe cardiac arrhythmias that cause sudden death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106632-02
Application #
8209146
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2011-01-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$533,096
Indirect Cost
$174,329
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Leo-Macias, Alejandra; Agullo-Pascual, Esperanza; Delmar, Mario (2016) The cardiac connexome: Non-canonical functions of connexin43 and their role in cardiac arrhythmias. Semin Cell Dev Biol 50:13-21
Leo-Macias, Alejandra; Agullo-Pascual, Esperanza; Sanchez-Alonso, Jose L et al. (2016) Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc. Nat Commun 7:10342
Dubash, Adi D; Kam, Chen Y; Aguado, Brian A et al. (2016) Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes. J Cell Biol 212:425-38
Delmar, Mario (2015) Channels, arrhythmias, and … the search for the impossible? Trends Cardiovasc Med 25:497-8
Delmar, Mario; Morley, Gregory E (2015) Genetically Encoded Voltage Indicators: Mapping Cardiac Electrical Activity Under a New Light. Circ Res 117:390-1
Lin, Xianming; O'Malley, Heather; Chen, Chunling et al. (2015) Scn1b deletion leads to increased tetrodotoxin-sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts. J Physiol 593:1389-407
Leo-Macías, Alejandra; Liang, Feng-Xia; Delmar, Mario (2015) Ultrastructure of the intercellular space in adult murine ventricle revealed by quantitative tomographic electron microscopy. Cardiovasc Res 107:442-52
Cerrone, Marina; Delmar, Mario (2014) Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome. Trends Cardiovasc Med 24:184-90
Agullo-Pascual, Esperanza; Cerrone, Marina; Delmar, Mario (2014) Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome. FEBS Lett 588:1322-30
Agullo-Pascual, Esperanza; Lin, Xianming; Leo-Macias, Alejandra et al. (2014) Super-resolution imaging reveals that loss of the C-terminus of connexin43 limits microtubule plus-end capture and NaV1.5 localization at the intercalated disc. Cardiovasc Res 104:371-81

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