Loss of Plakophilin-2 Expression Leads to Decreased Sodium Current and Slower Conduction Velocity in Cultured Cardiac Myocytes

Abstract

Key Words: plakophilin-2 Ⅲ intercalated disc Ⅲ arrhythmogenic right ventricular cardiomyopathy Ⅲ cardiac desmosomes A high-resolution image of the site of end-end contact between cardiomyocytes reveals an electron-dense organization called "the intercalated disc." Its classic definition involves 3 structures: desmosomes and adherens junctions, providing mechanical coupling; and gap junctions, allowing electric/metabolic synchronization between cells. Recent studies show that other molecules, not directly involved in intercellular coupling, also reside preferentially at the intercalated disc. Among them is Na V 1.5, the major ␣ subunit of the cardiac sodium channel. 1 Here, we ask whether Na v 1.5 and the desmosomal protein plakophilin-2 (PKP2) coexist in the same molecular complex and whether loss of PKP2 expression affects (1) the amplitude and kinetics of the sodium current and (2) action potential propagation in a monolayer of cardiomyocytes. Our data demonstrate a functional crosstalk between a protein defined in the context of intercellular junctions (PKP2) and another protein that is fundamental to the electrical behavior of the single myocyte.

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

“…In the intercalated disc (ID) region, Na V 1.5 colocalizes with N‐cadherin, ankyrin G, plakophilin‐2, and synapse‐associated protein 97, whereas Na V 1.5‐based channels located at the lateral membrane (LM) of the cardiomyocyte associate primarily with the dystrophin‐syntrophin complex 8, 9. Remodeling of region‐specific proteins may affect Na V 1.5 locally and lead to disturbances in I Na , conduction abnormalities, and arrhythmias 10, 11, 12, 13…”

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls

“…13 Experimental and clinical data suggest that other non-junctional cellular structures like the voltage-gated sodium channel (Nav 1.5), the sarcolemmal calcium channel regulating molecule PLN, and structural molecules are linked to desmosomes. 14 Especially PLN phosphorylation has been reported to play a key role in the pathophysiology of heart failure. 15 Taken together, various cellular pathways, particularly electromechanical cell-to-cell coupling, inflammation, apoptosis, adipogenesis and fibrosis seem to be involved in the pathophysiology of ARVC/D, but the interactions are not fully understood.…”

A novel kind of tumor type-characteristic junction: plakophilin-2 as a major protein of adherens junctions in cardiac myxomata

“…In the latter it is necessary for heart formation and for the onset and coordination of rhythmic heart beat, 18,[44][45][46][47][48] be it directly or indirectly (for further involvements of sodium channels or gap junctions, see also recent knockdown experiments). [49][50][51][52] Most impressive in the discussions about possible functional roles of Pkp2 are certainly the recent reports that cardiac Pkp2 is by far the most sensitive protein, which in mutated forms can contribute to arrhythmogenic ventricular cardiomyopathies (ARVCs). [46][47][48][49][50][51][52][53] Moreover, in Pkp2 gene knockdown experiments, it has also been shown that its stabilizing effect on cell-cell adhesion in rat cardiomyocyte cultures is so important that a reduction in Pkp2 can result in a complete separation of the two junctional membranes.…”

“…[46][47][48][49][50][51][52][53] Moreover, in Pkp2 gene knockdown experiments, it has also been shown that its stabilizing effect on cell-cell adhesion in rat cardiomyocyte cultures is so important that a reduction in Pkp2 can result in a complete separation of the two junctional membranes. [49][50][51][52] Thus, in myxoma tumors growing in a very viscous, mucoid-gelatinous matrix, the acquisition of Pkp2 to the adherens junctions may have an important stabilizing effect and strengthen cell-cell adhesions, in particular those connecting the long and thin cell processes.…”