PCP4 regulates Purkinje cell excitability and cardiac rhythmicity

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

doi:10.1172/jci77495

Cited by 48 publications

(51 citation statements)

References 39 publications

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“…Furthermore, RNA-Seq data from isolated cardiac Purkinje cells and working ventricular myocardium reported Mybphl expression as enriched in Purkinje cells (53.23 ± 26 FPKM in Purkinje cells vs 6.43 ± 3.37 FPKM in ventricular cells) 47 . This data, along with the observation of ventricular arrhythmias in Mybphl null mice and ventricular Mybphl -driven LacZ puncta, support the hypothesis that Mybphl is expressed in specific and critical locations in the ventricular conduction system.…”

Section: Discussionmentioning

confidence: 99%

Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

et al. 2017

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Rationale/Objective Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. Methods/Results Whole genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. Results Whole genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding myosin-binding protein-H like (MyBP-HL), a novel member of the myosin binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament-associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria as well as in discrete puncta throughout the right ventricular wall and septum. Telemetric ECG recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice. Conclusions The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

et al. 2017

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“…The Fishman lab has gone on to use CNTN-2 as a powerful tool to help identify other potentially critical proteins that are in Purkinje cells(PCs) and not in ventricular cells (eg. 14,15 ).…”

Section: Introductionmentioning

confidence: 99%

Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015

2016

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Purkinje fibers/cells continue to be a focus of arrhythmologists. Here we review several new ideas that have emerged in the literature and fold them into important new points. These points include some proteins in Purkinje cells that are specific to Purkinjes, pacemaker function in Purkinje may be similar to that of the sinus node cell, sink-source concerns about tracts/sheets of Purkinje fibers, role of Ito in arrhythmias and genetic lesions in Purkinjes and their high impact on cardiac rhythm. Although new ideas about the remodeled Purkinje cell are not the focus of this review, one can easily imagine how Purkinjes and their function may be altered in diseased hearts.

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“…Kim et al [59] found that PCP-4 binds calmodulin, resulting in a 50-fold increase in calcium binding rate. The presence of calmodulin binding with calcium activates CaMKII.…”

Section: Future Outlook: Pcp-4 the Linkmentioning

confidence: 99%

“…Downregulation of PCP-4 in disease models: phenylephrine infusion and transverse aortic constriction, showed a proarrhythmogenic cascade, increasing pCaMKII expression and intracellular calcium. Therefore PCP-4 inhibits CaMKII activity and downregulation of PCP-4 relieves this inhibition resulting in increased intracellular calcium and pro-arrhythmic behavior [59].…”

Section: Future Outlook: Pcp-4 the Linkmentioning

confidence: 99%

Resuscitation of a dead cardiomyocyte

2015

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Although cardiac resuscitation can revive the whole body, the mechanisms are unclear. To this end, we propose that reviving a dead/dysfunctional cardiomyocyte will shed light on resuscitation mechanisms and pave the way to treat cardiac myopathies. The degradation of the myocyte cytoskeleton by the proteasome system which involves calpains, ubiquitin, caspases and matrix metalloproteases is the main focus of this review. The activation of calpains beyond the calpastatin-mediated inhibition due to extensive calcium harbor can lead to titin degradation, damage to the sarcomere and contractile dysfunction. The ubiquitin proteasome system can disturb the protein homeostasis within the cell and generate a dysfunctional myocyte. The matrix metalloproteases disrupt the collagen/elastin ratio and connexins to generate arrhythmias. The concept of cardiac resuscitation stems from protecting the myocyte cytoskeleton and keeping the protein homeostasis intact through management of the degradation machinery. In this regard, proteasome inhibitors for the degradation machinery have an elegant space. Recently exosomes have been identified potentially, as carriers of microRNAs or proteins that can modify the target cells. Exosomes loaded with the inhibitor "cargo" which comprises microRNAs, siRNAs or proteins to inhibit the degradation machinery can be a method of choice for cardiac resuscitation-a process difficult to execute.

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PCP4 regulates Purkinje cell excitability and cardiac rhythmicity

Cited by 48 publications

References 39 publications

Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015

Resuscitation of a dead cardiomyocyte

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