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.
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.
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|Cerrone, Marina; Delmar, Mario (2014) Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome. Trends Cardiovasc Med 24:184-90|
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|Lubkemeier, Indra; Requardt, Robert Pascal; Lin, Xianming et al. (2013) Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels. Basic Res Cardiol 108:348|
|Agullo-Pascual, Esperanza; Reid, Dylan A; Keegan, Sarah et al. (2013) Super-resolution fluorescence microscopy of the cardiac connexome reveals plakophilin-2 inside the connexin43 plaque. Cardiovasc Res 100:231-40|
|Bhargava, Anamika; Lin, Xianming; Novak, Pavel et al. (2013) Super-resolution scanning patch clamp reveals clustering of functional ion channels in adult ventricular myocyte. Circ Res 112:1112-20|
|Chkourko, Halina S; Guerrero-Serna, Guadalupe; Lin, Xianming et al. (2012) Remodeling of mechanical junctions and of microtubule-associated proteins accompany cardiac connexin43 lateralization. Heart Rhythm 9:1133-1140.e6|
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