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

PCP4 regulates Purkinje cell excitability and cardiac rhythmicity

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 4

Effect of Pcp4-null mutation on PC AP characteristics and calcium currents.

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Effect of Pcp4-null mutation on PC AP characteristics and calcium curren...
(A) Representative AP tracings from control and Pcp4-null PCs. Comparison of APD50 and APD90 of repolarization, resting membrane potential and AP amplitude between Pcp4-null and control PCs. (B) Comparison of current-voltage (I-V) relationship of ICa in Pcp4-null and control PCs in the presence or absence of AIP. Peak current density was plotted and used to assess significant differences among experimental groups. Representative whole-cell recordings of ICa evoked by voltage steps from –40 to +40 mV in 10-mV increments from a holding potential of –50 mV with a 30-ms prepulse to –30 mV. (C) Comparison of steady state inactivation curve of ICa in Pcp4-null and control PCs in the presence or absence of AIP. The voltage at half-inactivation (V1/2) was plotted and used to assess significant differences among experimental groups. Representative whole-cell recordings of ICa evoked by voltage clamp at 0 mV after a 30-ms prepulse to –30 mV from holding potentials stepped from –60 to +15 mV for 1 second in 5-mV increments. For A–C, n = 10–15 cells per group. Data represent mean ± SEM. *P < 0.05.