title: 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.forename: Eugene E
authors.initials: EE
authors.lastname: Kim
authors.forename: Akshay
authors.initials: A
authors.lastname: Shekhar
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Xianming
authors.initials: X
authors.lastname: Lin
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D015870:Gene Expression; D006801:Humans; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011690:Purkinje Fibers / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; C489091:Pcp4 protein, mouse