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PCP4 regulates Purkinje cell excitability and cardiac rhythmicity
Eugene E. Kim, … , Mario Delmar, Glenn I. Fishman
Eugene E. Kim, … , Mario Delmar, Glenn I. Fishman
Published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):5027-5036. https://doi.org/10.1172/JCI77495.
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Research Article Cardiology Article has an altmetric score of 14

PCP4 regulates Purkinje cell excitability and cardiac rhythmicity

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Abstract

Cardiac Purkinje cells are important triggers of ventricular arrhythmias associated with heritable and acquired syndromes; however, the mechanisms responsible for this proarrhythmic behavior are incompletely understood. Here, through transcriptional profiling of genetically labeled cardiomyocytes, we identified expression of Purkinje cell protein-4 (Pcp4), a putative regulator of calmodulin and Ca2+/calmodulin-dependent kinase II (CaMKII) signaling, exclusively within the His-Purkinje network. Using Pcp4-null mice and acquired cardiomyopathy models, we determined that reduced expression of PCP4 is associated with CaMKII activation, abnormal electrophysiology, dysregulated intracellular calcium handling, and proarrhythmic behavior in isolated Purkinje cells. Pcp4-null mice also displayed profound autonomic dysregulation and arrhythmic behavior in vivo. Together, these results demonstrate that PCP4 regulates cardiac excitability through both Purkinje cell–autonomous and central mechanisms and identify this modulator of CaMKII signaling as a potential arrhythmia-susceptibility candidate.

Authors

Eugene E. Kim, Akshay Shekhar, Jia Lu, Xianming Lin, Fang-Yu Liu, Jie Zhang, Mario Delmar, Glenn I. Fishman

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Figure 3

Transmural expression patterns of tCaMKII and pCaMKII in Pcp4-null and control hearts.

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Transmural expression patterns of tCaMKII and pCaMKII in Pcp4-null and c...
(A) Representative immunofluorescence staining of tCaMKII and pCaMKII in Pcp4-null and control hearts. CNTN2 expression identifies PCs. (B and C) Quantitative assessment of the abundance of pCaMKII and tCaMKII and the ratio of pCaMKII/tCaMKII as assessed by pixel intensity. (B) Intensity measurements were plotted (in arbitrary units) as a function of distance from the endocardium in the left ventricular free-wall myocardium. (C) Comparison of intensity measurements (plotted in arbitrary units) within distinct compartments of Pcp4-null and control animals: Purkinje network (PC; 10–40 μm from endocardium), subendocardial VMs (ENDO VM; 75–125 μm from endocardium), and midmyocardial VMs (MID VM; 250–300 μm from endocardium). Scale bar: 100 μm. Data represent mean ± SEM. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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