Publications by authors named "Jeanne M Nerbonne"

111 Publications

Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 2: Population and Clinical Considerations.

Circ Arrhythm Electrophysiol 2021 11 1;14(11):e010190. Epub 2021 Nov 1.

National Heart, Lung, and Blood Institute, Bethesda, MD (R.C.B.).

Sudden cardiac death (SCD) is the sudden, unexpected death due to abrupt loss of heart function secondary to cardiovascular disease. In certain populations living with cardiovascular disease, SCD follows a distinct 24-hour pattern in occurrence, suggesting day/night rhythms in behavior, the environment, and endogenous circadian rhythms result in daily spans of increased vulnerability. The National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death to identify fundamental questions regarding the role of the circadian rhythms in SCD. Part 2 summarizes research gaps and opportunities in the areas of population and clinical research identified in the workshop. Established research supports a complex interaction between circadian rhythms and physiological responses that increase the risk for SCD. Moreover, these physiological responses themselves are influenced by several biological variables, including the type of cardiovascular disease, sex, age, and genetics, as well as environmental factors. The emergence of new noninvasive biotechnological tools that continuously measure key cardiovascular variables, as well as the identification of biomarkers to assess circadian rhythms, hold promise for generating large-scale human data sets that will delineate which subsets of individuals are most vulnerable to SCD. Additionally, these data will improve our understanding of how people who suffer from circadian disruptions develop cardiovascular diseases that increase the risk for SCD. Emerging strategies to identify new biomarkers that can quantify circadian health (eg, environmental, behavioral, and internal misalignment) may lead to new interventions and therapeutic targets to prevent the progression of cardiovascular diseases that cause SCD.
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http://dx.doi.org/10.1161/CIRCEP.121.010190DOI Listing
November 2021

Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 1: Basic and Translational Aspects.

Circ Arrhythm Electrophysiol 2021 11 1;14(11):e010181. Epub 2021 Nov 1.

National Heart, Lung, and Blood Institute, Bethesda, MD (R.C.B.).

Sudden cardiac death (SCD), the unexpected death due to acquired or genetic cardiovascular disease, follows distinct 24-hour patterns in occurrence. These 24-hour patterns likely reflect daily changes in arrhythmogenic triggers and the myocardial substrate caused by day/night rhythms in behavior, the environment, and endogenous circadian mechanisms. To better address fundamental questions regarding the circadian mechanisms, the National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death. We present a 2-part report of findings from this workshop. Part 1 summarizes the workshop and serves to identify research gaps and opportunities in the areas of basic and translational research. Among the gaps was the lack of standardization in animal studies for reporting environmental conditions (eg, timing of experiments relative to the light dark cycle or animal housing temperatures) that can impair rigor and reproducibility. Workshop participants also pointed to uncertainty regarding the importance of maintaining normal circadian rhythmic synchrony and the potential pathological impact of desynchrony on SCD risk. One related question raised was whether circadian mechanisms can be targeted to reduce SCD risk. Finally, the experts underscored the need for studies aimed at determining the physiological importance of circadian clocks in the many different cell types important to normal heart function and SCD. Addressing these gaps could lead to new therapeutic approaches/molecular targets that can mitigate the risk of SCD not only at certain times but over the entire 24-hour period.
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http://dx.doi.org/10.1161/CIRCEP.121.010181DOI Listing
November 2021

Identification of structures for ion channel kinetic models.

PLoS Comput Biol 2021 08 16;17(8):e1008932. Epub 2021 Aug 16.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, United States of America.

Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium currents and human left ventricular fast transient outward potassium currents. Successful models identified with this approach have certain characteristics in common, suggesting that aspects of the model topology are determined by the experimental data. Incorporating these channel models into cell and tissue simulations to assess model performance within protocols that were not used for training provided validation and further narrowing of the number of acceptable models. The success of this approach suggests a channel model creation pipeline may be feasible where the structure of the model is not specified a priori.
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http://dx.doi.org/10.1371/journal.pcbi.1008932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389848PMC
August 2021

Controlling the Traffic to Keep the Beat: Targeting of Myocardial Sodium Channels.

Circ Res 2021 07 22;129(3):366-368. Epub 2021 Jul 22.

Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University Medical School, St. Louis, MO.

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http://dx.doi.org/10.1161/CIRCRESAHA.121.319653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318379PMC
July 2021

Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits.

JCI Insight 2021 08 9;6(15). Epub 2021 Aug 9.

Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.

Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib drug-binding site, F1760, affected but did not abolish the modulation of drug block by NaVβ1/β3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (NaVβ1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that NaVβ1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.
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http://dx.doi.org/10.1172/jci.insight.143092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410097PMC
August 2021

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.

J Gen Physiol 2021 05;153(5)

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO.

Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.
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http://dx.doi.org/10.1085/jgp.202012787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054178PMC
May 2021

Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites.

J Gen Physiol 2021 02;153(2)

Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France.

Phosphorylation of the voltage-gated Na+ (NaV) channel NaV1.5 regulates cardiac excitability, yet the phosphorylation sites regulating its function and the underlying mechanisms remain largely unknown. Using a systematic, quantitative phosphoproteomic approach, we analyzed NaV1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 channel expression and gating. The phosphorylated serines S664 and S667 regulate the voltage dependence of channel activation in a cumulative manner, whereas the nearby S671, the phosphorylation of which is increased in failing hearts, regulates cell surface NaV1.5 expression and peak Na+ current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular NaV1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of NaV1.5 channels is highly complex, site specific, and dynamic.
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http://dx.doi.org/10.1085/jgp.202012646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797897PMC
February 2021

Polycystin 2 is increased in disease to protect against stress-induced cell death.

Sci Rep 2020 01 15;10(1):386. Epub 2020 Jan 15.

Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, 06510, United States of America.

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases.
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http://dx.doi.org/10.1038/s41598-019-57286-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962458PMC
January 2020

The Role of the Voltage-Gated Potassium Channel Proteins Kv8.2 and Kv2.1 in Vision and Retinal Disease: Insights from the Study of Mouse Gene Knock-Out Mutations.

eNeuro 2019 Jan-Feb;6(1). Epub 2019 Feb 25.

Centre for Ophthalmology and Vision Science, Lions Eye Institute, The University of Western Australia, Perth, Western Australia 6009, Australia.

Mutations in the gene, which encodes the voltage-gated K channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNELpositive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K channels in the generation of the a-, b-, and c-wave components of the ERG.
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http://dx.doi.org/10.1523/ENEURO.0032-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393689PMC
May 2019

Regional differences in the expression of tetrodotoxin-sensitive inward Ca and outward Cs/K currents in mouse and human ventricles.

Channels (Austin) 2019 12;13(1):72-87

a Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division , Washington University School of Medicine , St. Louis , MO , USA.

Tetrodotoxin (TTX) sensitive inward Ca currents, I, have been identified in cardiac myocytes from several species, although it is unclear if I is expressed in all cardiac cell types, and if I reflects Ca entry through the main, Nav1.5-encoded, cardiac Na (Nav) channels. To address these questions, recordings were obtained with 2 mm Ca and 0 mm Na in the bath and 120 mm Cs in the pipettes from myocytes isolated from adult mouse interventricular septum (IVS), left ventricular (LV) endocardium, apex, and epicardium and from human LV endocardium and epicardium. On membrane depolarizations from a holding potential of -100 mV, I was identified in mouse IVS and LV endocardial myocytes and in human LV endocardial myocytes, whereas only TTX-sensitive outward Cs/K currents were observed in mouse LV apex and epicardial myocytes and human LV epicardial myocytes. The inward Ca, but not the outward Cs/K, currents were blocked by mm concentrations of MTSEA, a selective blocker of cardiac Nav1.5-encoded Na channels. In addition, in Nav1.5-expressing tsA-201 cells, I was observed in 3 (of 20) cells, and TTX-sensitive outward Cs/K currents were observed in the other (17) cells. The time- and voltage-dependent properties of the TTX-sensitive inward Ca and outward Cs/K currents recorded in Nav1.5-expressing tsA-201 were indistinguishable from native currents in mouse and human cardiac myocytes. Overall, the results presented here suggest marked regional, cell type-specific, differences in the relative ion selectivity, and likely the molecular architecture, of native SCN5A-/Scn5a- (Nav1.5-) encoded cardiac Na channels in mouse and human ventricles.
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http://dx.doi.org/10.1080/19336950.2019.1568146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380286PMC
December 2019

Regional Differences in mRNA and lncRNA Expression Profiles in Non-Failing Human Atria and Ventricles.

Sci Rep 2018 09 17;8(1):13919. Epub 2018 Sep 17.

Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.

The four chambers of the human heart play distinct roles in the maintenance of normal cardiac function, and are differentially affected by inherited/acquired cardiovascular disease. To probe the molecular determinants of these functional differences, we examined mRNA and lncRNA expression profiles in the left (LA) and right (RA) atria, the left (LV) and right (RV) ventricles, and the interventricular septum (IVS) of non-failing human hearts (N = 8). Analysis of paired atrial and ventricular samples (n = 40) identified 5,747 mRNAs and 2,794 lncRNAs that were differentially (>1.5 fold; FDR < 0.05) expressed. The largest differences were observed in comparisons between the atrial (RA/LA) and ventricular (RV/LV/IVS) samples. In every case (e.g., LA vs LV, LA vs RV, etc.), >2,300 mRNAs and >1,200 lncRNAs, corresponding to 17-28% of the total transcripts, were differentially expressed. Heterogeneities in mRNA/lncRNA expression profiles in the LA and RA, as well as in the LV, RV and IVS, were also revealed, although the numbers of differentially expressed transcripts were substantially smaller. Gender differences in mRNA and lncRNA expression profiles were also evident in non-failing human atria and ventricles. Gene ontology classification of differentially expressed gene sets revealed chamber-specific enrichment of numerous signaling pathways.
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http://dx.doi.org/10.1038/s41598-018-32154-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141608PMC
September 2018

Circulating long noncoding RNA DKFZP434I0714 predicts adverse cardiovascular outcomes in patients with end-stage renal disease.

Int J Cardiol 2019 Feb 7;277:212-219. Epub 2018 Aug 7.

Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Background: Cardiovascular (CV) diseases are major causes of mortality in uremic patients. Conventional risk factors fail to identify uremic patients with increased propensity for adverse CV outcomes. We aimed to test the hypothesis that circulating long noncoding RNAs (lncRNAs) could be a prognostic marker to predict adverse CV outcomes in uremic patients.

Methods And Results: Plasma lncRNAs were profiled in patients with end-stage renal disease (ESRD, n = 28) or chronic kidney disease (CKD, n = 8) and in healthy (n = 12) subjects by RNA sequencing. A total of 179 lncRNAs were significantly dysregulated with ESRD; the expression signature of plasma lncRNAs distinguished ESRD from both CKD and control samples. Analysis on a microarray dataset obtained from renal biopsy samples of patients with advanced kidney disease (GSE66494) revealed that a significant proportion of plasma lncRNAs (30.7%) and mRNAs (49.5%) dysregulated with uremia were similarly dysregulated in diseased kidneys, suggesting that plasma RNA profiles mirror the transcriptomal changes in diseased kidney tissues. Further analyses identified eight plasma lncRNAs as potential predictors of adverse CV outcomes in uremic patients. Validation study in an independent cohort of ESRD patients (n = 111) confirmed that elevated plasma lncRNA DKFZP434I0714 is a significant independent predictor of adverse CV outcomes in uremic patients. Additional experiments demonstrated the functional involvement of DKFZP434I0714 in the pathogenesis of endothelial dysfunction.

Conclusions: In summary, plasma lncRNA expression signature reflects the disease states of uremia. Elevated plasma levels of lncRNA DKFZP434I0714 in uremic patients portend a worse CV outcome and warrant closer monitoring and more aggressive management.
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http://dx.doi.org/10.1016/j.ijcard.2018.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340736PMC
February 2019

Voltage-gated sodium currents in cerebellar Purkinje neurons: functional and molecular diversity.

Cell Mol Life Sci 2018 Oct 7;75(19):3495-3505. Epub 2018 Jul 7.

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Purkinje neurons, the sole output of the cerebellar cortex, deliver GABA-mediated inhibition to the deep cerebellar nuclei. To subserve this critical function, Purkinje neurons fire repetitively, and at high frequencies, features that have been linked to the unique properties of the voltage-gated sodium (Nav) channels expressed. In addition to the rapidly activating and inactivating, or transient, component of the Nav current (I) present in many types of central and peripheral neurons, Purkinje neurons, also expresses persistent (I) and resurgent (I) Nav currents. Considerable progress has been made in detailing the biophysical properties and identifying the molecular determinants of these discrete Nav current components, as well as defining their roles in the regulation of Purkinje neuron excitability. Here, we review this important work and highlight the remaining questions about the molecular mechanisms controlling the expression and the functioning of Nav currents in Purkinje neurons. We also discuss the impact of the dynamic regulation of Nav currents on the functioning of individual Purkinje neurons and cerebellar circuits.
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http://dx.doi.org/10.1007/s00018-018-2868-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123253PMC
October 2018

Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation.

Circ Res 2018 04 13;122(8):1052-1068. Epub 2018 Mar 13.

From the Department and Graduate Institute of Pharmacology (Y.-C.S., C.-L.C., H.-C.W., C.-T.H., J.-Y.N., H.-J.C., T.-H.L., Y.-S.T., K.-C.Y.), Department and Graduate Institute of Medical Education and Bioethics (C.-C.W.), and Department and Graduate Institute of Physiology (S.-L.L.), National Taiwan University College of Medicine, Taipei; Department of Developmental Biology (J.M.N.) and Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine (Y.Z., R.L.M., E.M.K., K.A.Y., J.M.N.), Washington University School of Medicine, St Louis, MO; Department of Medicine, University of Chicago, IL (Y.F.); Department of Surgery (C.-N.C.), Division of Nephrology, Department of Internal Medicine (S.-L.L.), and Division of Cardiology, Department of Internal Medicine (C.-C.W., K.-C.Y.), National Taiwan University Hospital, Taipei.

Rationale: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting coexpression gene network analysis on RNA sequencing data from failing human heart, we identified TXNDC5 (thioredoxin domain containing 5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum protein, as a potential novel mediator of cardiac fibrosis, and we completed experiments to test this hypothesis directly.

Objective: The objective of this study was to determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis.

Methods And Results: RNA sequencing and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles and in hypertrophied/failing mouse left ventricle. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor β1 and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under transforming growth factor β1 stimulation in vitro. Knockdown of attenuated transforming growth factor β1-induced hCF activation and ECM protein upregulation independent of SMAD3 (SMAD family member 3), whereas increasing expression of triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing c-Jun N-terminal kinase activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. Transforming growth factor β1-induced TXNDC5 upregulation in hCF was dependent on endoplasmic reticulum stress and activating transcription factor 6-mediated transcriptional control. Targeted disruption of in mice () revealed protective effects against isoproterenol-induced cardiac hypertrophy, reduced fibrosis (by ≈70%), and markedly improved left ventricle function; post-isoproterenol left ventricular ejection fraction was 59.1±1.5 versus 40.1±2.5 (<0.001) in versus wild-type mice, respectively.

Conclusions: The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against β agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899016PMC
April 2018

Differential Expression and Remodeling of Transient Outward Potassium Currents in Human Left Ventricles.

Circ Arrhythm Electrophysiol 2018 01;11(1):e005914

From the Cardiovascular Division, Department of Medicine (E.K.J., S.J.S., W.W., E.J.D., Y.Z., E.M.K., K.A.Y., J.M.N.) and Department of Developmental Biology (J.M.N.), Washington University School of Medicine, St. Louis, MO.

Background: Myocardial, transient, outward currents, , have been shown to play pivotal roles in action potential (AP) repolarization and remodeling in animal models. The properties and contribution of to left ventricular (LV) repolarization in the human heart, however, are poorly defined.

Methods And Results: Whole-cell, voltage-clamp recordings, acquired at physiological (35°C to 37°C) temperatures, from myocytes isolated from the LV of nonfailing human hearts identified 2 distinct transient currents, () and (), with significantly (<0.0001) different rates of recovery from inactivation and pharmacological sensitives: recovers in ≈10 ms, 100× faster than , and is selectively blocked by the Kv4 channel toxin, SNX-482. Current-clamp experiments revealed regional differences in AP waveforms, notably a phase 1 notch in LV subepicardial myocytes. Dynamic clamp-mediated addition/removal of modeled human ventricular , resulted in hyperpolarization or depolarization, respectively, of the notch potential, whereas slowing the rate of inactivation resulted in AP collapse. AP-clamp experiments demonstrated that changes in notch potentials modified the time course and amplitudes of voltage-gated Ca currents, . In failing LV subepicardial myocytes, was reduced and was increased, notch and plateau potentials were depolarized (<0.0001) and AP durations were prolonged (<0.001).

Conclusions: and are differentially expressed in nonfailing human LV, contributing to regional heterogeneities in AP waveforms. regulates notch and plateau potentials and modulates the time course and amplitude of . Slowing inactivation results in dramatic AP shortening. Remodeling of in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.
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http://dx.doi.org/10.1161/CIRCEP.117.005914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775893PMC
January 2018

C-terminal phosphorylation of Na1.5 impairs FGF13-dependent regulation of channel inactivation.

J Biol Chem 2017 10 7;292(42):17431-17448. Epub 2017 Sep 7.

From the l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes 44007, France,

Voltage-gated Na (Na) channels are key regulators of myocardial excitability, and Ca/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in Na1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of Na1.5 subunits associated with these arrhythmogenic disorders and the associated channel regulatory defects remain unknown. Here, we undertook phosphoproteomic analyses to identify and quantify the phosphorylation sites in the Na1.5 proteins purified from adult WT and failing CaMKIIδ-overexpressing (CaMKIIδ-Tg) mouse ventricles. Of 19 native Na1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδ-Tg compared with the WT ventricles. We then tested the hypothesis that phosphorylation at these two sites impairs fibroblast growth factor 13 (FGF13)-dependent regulation of Na1.5 channel inactivation. Whole-cell voltage-clamp analyses in HEK293 cells demonstrated that FGF13 increases Na1.5 channel availability and decreases late Na current, two effects that were abrogated with Na1.5 mutants mimicking phosphorylation at both sites. Additional co-immunoprecipitation experiments revealed that FGF13 potentiates the binding of calmodulin to Na1.5 and that phosphomimetic mutations at both sites decrease the interaction of FGF13 and, consequently, of calmodulin with Na1.5. Together, we have identified two novel native phosphorylation sites in the C terminus of Na1.5 that impair FGF13-dependent regulation of channel inactivation and may contribute to CaMKIIδ-dependent arrhythmogenic disorders in failing hearts.
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http://dx.doi.org/10.1074/jbc.M117.787788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655519PMC
October 2017

Mechanisms of noncovalent β subunit regulation of Na channel gating.

J Gen Physiol 2017 08 7;149(8):813-831. Epub 2017 Aug 7.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO

Voltage-gated Na (Na) channels comprise a macromolecular complex whose components tailor channel function. Key components are the non-covalently bound β1 and β3 subunits that regulate channel gating, expression, and pharmacology. Here, we probe the molecular basis of this regulation by applying voltage clamp fluorometry to measure how the β subunits affect the conformational dynamics of the cardiac Na channel (Na1.5) voltage-sensing domains (VSDs). The pore-forming Na1.5 α subunit contains four domains (DI-DIV), each with a VSD. Our results show that β1 regulates Na1.5 by modulating the DIV-VSD, whereas β3 alters channel kinetics mainly through DIII-VSD interaction. Introduction of a quenching tryptophan into the extracellular region of the β3 transmembrane segment inverted the DIII-VSD fluorescence. Additionally, a fluorophore tethered to β3 at the same position produced voltage-dependent fluorescence dynamics strongly resembling those of the DIII-VSD. Together, these results provide compelling evidence that β3 binds proximally to the DIII-VSD. Molecular-level differences in β1 and β3 interaction with the α subunit lead to distinct activation and inactivation recovery kinetics, significantly affecting Na channel regulation of cell excitability.
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http://dx.doi.org/10.1085/jgp.201711802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560778PMC
August 2017

Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior.

eNeuro 2017 May-Jun;4(3). Epub 2017 May 23.

Departments of Developmental Biology and Internal Medicine Washington University School of Medicine, Washington University, St. Louis, MO 63130.

Rapidly activating and inactivating A-type K currents (I) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the knockdown of Kv4.1 significantly ( < 0.0001) increased mean ± SEM repetitive firing rates in SCN neurons during the day (6.4 ± 0.5 Hz) and at night (4.3 ± 0.6 Hz), compared with nontargeted shRNA-expressing SCN neurons (day: 3.1 ± 0.5 Hz; night: 1.6 ± 0.3 Hz). I was also significantly ( < 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 ± 11.8 pA/pF; night: 55.3 ± 7.7 pA/pF), compared with nontargeted shRNA-expressing (day: 121.7 ± 10.2 pA/pF; night: 120.6 ± 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and I was larger at night. In addition, Kv4.1-targeted shRNA expression significantly ( < 0.001) increased mean ± SEM nighttime input resistance (R; 2256 ± 166 MΩ), compared to nontargeted shRNA-expressing SCN neurons (1143 ± 93 MΩ). Additional experiments revealed that acute knockdown of Kv4.1 significantly ( < 0.01) shortened, by ∼0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded I channels in regulating circadian rhythms in neuronal excitability and behavior.
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http://dx.doi.org/10.1523/ENEURO.0377-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440767PMC
March 2018

Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance.

Cell Rep 2017 04;19(3):532-544

Departments of Developmental Biology and Internal Medicine , Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

The resurgent component of voltage-gated Na (Nav) currents, I, has been suggested to provide the depolarizing drive for high-frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory Navβ4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (Navβ4) on I and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4b animals have deficits in motor coordination and balance and that firing rates in Scn4b Purkinje neurons are markedly attenuated. Acute, in vivo short hairpin RNA (shRNA)-mediated "knockdown" of Navβ4 in adult Purkinje neurons also reduced spontaneous and evoked firing rates. Dynamic clamp-mediated addition of I partially rescued firing in Scn4b Purkinje neurons. Voltage-clamp experiments revealed that I was reduced (by ∼50%), but not eliminated, in Scn4b Purkinje neurons, revealing that additional mechanisms contribute to generation of I.
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http://dx.doi.org/10.1016/j.celrep.2017.03.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473293PMC
April 2017

Early remodeling of repolarizing K currents in the αMHC mouse model of familial hypertrophic cardiomyopathy.

J Mol Cell Cardiol 2017 02 13;103:93-101. Epub 2017 Jan 13.

Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Medicine, Washington University Medical School, St. Louis, MO 63110-1093, USA. Electronic address:

Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC mouse line in which one αMHC allele harbors a common HCM mutation (in βMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K (Kv) current (I) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, I, I and I, were significantly lower in αMHC, compared with WT, septum cells, whereas I amplitudes were similar. The amplitudes/densities of I and I were also lower in αMHC, compared with WT, LV wall and LV apex myocytes, whereas I was attenuated in αMHC LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) αMHC mice, although this transcriptional remodeling was not correlated with the observed decreases in K current amplitudes.
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http://dx.doi.org/10.1016/j.yjmcc.2017.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398411PMC
February 2017

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics.

J Physiol 2017 04 5;595(7):2229-2252. Epub 2017 Jan 5.

Departments of Developmental Biology and Internal Medicine, Cardiovascular Division, Washington University Medical School, St Louis, MO, 63110, USA.

This is the second of the two White Papers from the fourth UC Davis Cardiovascular Symposium Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias (3-4 March 2016), a biennial event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was 'K channels and regulation', and the objectives of the conference were severalfold: (1) to identify current knowledge gaps; (2) to understand what may go wrong in the diseased heart and why; (3) to identify possible novel therapeutic targets; and (4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias. The sessions of the Symposium focusing on the functional roles of the cardiac K channel in health and disease, as well as K channels as therapeutic targets, were contributed by Ye Chen-Izu, Gideon Koren, James Weiss, David Paterson, David Christini, Dobromir Dobrev, Jordi Heijman, Thomas O'Hara, Crystal Ripplinger, Zhilin Qu, Jamie Vandenberg, Colleen Clancy, Isabelle Deschenes, Leighton Izu, Tamas Banyasz, Andras Varro, Heike Wulff, Eleonora Grandi, Michael Sanguinetti, Donald Bers, Jeanne Nerbonne and Nipavan Chiamvimonvat as speakers and panel discussants. This article summarizes state-of-the-art knowledge and controversies on the functional roles of cardiac K channels in normal and diseased heart. We endeavour to integrate current knowledge at multiple scales, from the single cell to the whole organ levels, and from both experimental and computational studies.
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http://dx.doi.org/10.1113/JP272883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374105PMC
April 2017

Training the Next Generation of Translational Cardiovascular Investigators: Is the Pipeline Half Full or Half Empty?

JACC Basic Transl Sci 2016 Oct 31;1(6):554-556. Epub 2016 Oct 31.

Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

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http://dx.doi.org/10.1016/j.jacbts.2016.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113424PMC
October 2016

Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents.

Circ Res 2016 Dec 3;119(12):1324-1338. Epub 2016 Oct 3.

Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Rationale: Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an induced Purkinje-like state characterized by prolonged action potential duration and expression of Purkinje-enriched genes.

Objective: To understand the mechanism by which canonical Notch signaling causes action potential prolongation.

Methods And Results: We find that endogenous Purkinje cells have reduced peak K current, I, and I when compared with ventricular myocytes. Consistent with partial reprogramming toward a Purkinje-like phenotype, Notch activation decreases peak outward K current density, as well as the outward K current components I and I,. Gene expression studies in Notch-activated ventricles demonstrate upregulation of Purkinje-enriched genes Contactin-2 and Scn5a and downregulation of K channel subunit genes that contribute to I and I. In contrast, inactivation of Notch signaling results in increased cell size commensurate with increased K current amplitudes and mimics physiological hypertrophy. Notch-induced changes in K current density are regulated at least in part via transcriptional changes. Chromatin immunoprecipitation demonstrates dynamic RBP-J (recombination signal binding protein for immunoglobulin kappa J region) binding and loss of active histone marks on K channel subunit promoters with Notch activation, and similar transcriptional and epigenetic changes occur in a heart failure model. Interestingly, there is a differential response in Notch target gene expression and cellular electrophysiology in left versus right ventricular cardiac myocytes.

Conclusions: In summary, these findings demonstrate a novel mechanism for regulation of voltage-gated potassium currents in the setting of cardiac pathology and may provide a novel target for arrhythmia drug design.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148677PMC
December 2016

Molecular Basis of Functional Myocardial Potassium Channel Diversity.

Card Electrophysiol Clin 2016 Jun 24;8(2):257-73. Epub 2016 Mar 24.

Department of Internal Medicine, Washington University Medical School, 660 South Euclid Avenue, Box 8086, St Louis, MO 63110, USA; Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110, USA. Electronic address:

Multiple types of voltage-gated K(+) and non-voltage-gated K(+) currents have been distinguished in mammalian cardiac myocytes based on differences in time-dependent and voltage-dependent properties and pharmacologic sensitivities. Many of the genes encoding voltage-gated K(+) (Kv) and non-voltage-gated K(+) (Kir and K2P) channel pore-forming and accessory subunits are expressed in the heart, and a variety of approaches have been, and continue to be, used to define the molecular determinants of native cardiac K(+) channels and to explore the molecular mechanisms controlling the diversity, regulation, and remodeling of these channels in the normal and diseased myocardium.
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http://dx.doi.org/10.1016/j.ccep.2016.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893780PMC
June 2016

Proteomic analysis of native cerebellar iFGF14 complexes.

Channels (Austin) 2016 Jul 18;10(4):297-312. Epub 2016 Feb 18.

e L'Institut du Thorax, INSERM UMR1087, CNRS UMR6291, Université de Nantes , Nantes , France.

Intracellular Fibroblast Growth Factor 14 (iFGF14) and the other intracellular FGFs (iFGF11-13) regulate the properties and densities of voltage-gated neuronal and cardiac Na(+) (Nav) channels. Recent studies have demonstrated that the iFGFs can also regulate native voltage-gated Ca(2+) (Cav) channels. In the present study, a mass spectrometry (MS)-based proteomic approach was used to identify the components of native cerebellar iFGF14 complexes. Using an anti-iFGF14 antibody, native iFGF14 complexes were immunoprecipitated from wild type adult mouse cerebellum. Parallel control experiments were performed on cerebellar proteins isolated from mice (Fgf14(-/-)) harboring a targeted disruption of the Fgf14 locus. MS analyses of immunoprecipitated proteins demonstrated that the vast majority of proteins identified in native cerebellar iFGF14 complexes are Nav channel pore-forming (α) subunits or proteins previously reported to interact with Nav α subunits. In contrast, no Cav channel α or accessory subunits were revealed in cerebellar iFGF14 immunoprecipitates. Additional experiments were completed using an anti-PanNav antibody to immunoprecipitate Nav channel complexes from wild type and Fgf14(-/-) mouse cerebellum. Western blot and MS analyses revealed that the loss of iFGF14 does not measurably affect the protein composition or the relative abundance of Nav channel interacting proteins in native adult mouse cerebellar Nav channel complexes.
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http://dx.doi.org/10.1080/19336950.2016.1153203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954571PMC
July 2016

Cardiac Mechano-Gated Ion Channels and Arrhythmias.

Circ Res 2016 Jan;118(2):311-29

From the National Heart and Lung Institute, Imperial College London, United Kingdom (R.P., P.K.); Departments of Developmental Biology and Internal Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (J.M.N.); Institute for Experimental Cardiovascular Medicine, University Heart Centre Freiburg/Bad Krozingen, Freiburg, Germany (R.P., P.K.).

Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret, and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, is exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intracardially and are, thus, maintained even in heart transplant recipients. Although mechanosensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechanotransduction have started to emerge. Mechano-gated ion channels are cardiac mechanoreceptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.305043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742365PMC
January 2016

Distinct Firing Properties of Vasoactive Intestinal Peptide-Expressing Neurons in the Suprachiasmatic Nucleus.

J Biol Rhythms 2016 Feb 27;31(1):57-67. Epub 2015 Dec 27.

Departments of Developmental Biology and Medicine, Washington University School of Medicine, Saint Louis, MO

The suprachiasmatic nucleus (SCN) regulates daily rhythms in physiology and behavior. Previous studies suggest a critical role for neurons expressing vasoactive intestinal peptide (VIP) in coordinating rhythmicity and synchronization in the SCN. Here we examined the firing properties of VIP-expressing SCN neurons in acute brain slices. Active and passive membrane properties were measured in VIP and in non-VIP neurons during the day and at night. Current-clamp recordings revealed that both VIP and non-VIP neurons were spontaneously active, with higher firing rates during the day than at night. Average firing frequencies, however, were higher in VIP neurons (3.1 ± 0.2 Hz, day and 2.4 ± 0.2 Hz, night) than in non-VIP neurons (1.8 ± 0.2 Hz, day and 0.9 ± 0.2 Hz, night), both day and night. The waveforms of individual action potentials in VIP and non-VIP neurons were also distinct. Action potential durations (APD50) were shorter in VIP neurons (3.6 ± 0.1 ms, day and 2.9 ± 0.1 ms, night) than in non-VIP neurons (4.4 ± 0.3 ms, day and 3.5 ± 0.2 ms, night) throughout the light-dark cycle. In addition, afterhyperpolarization (AHP) amplitudes were larger in VIP neurons (21 ± 0.8 mV, day and 24.9 ± 0.9 mV, night) than in non-VIP neurons (17.2 ± 1.1 mV, day and 20.5 ± 1.2 mV, night) during the day and at night. Furthermore, significant day/night differences were observed in APD50 and AHP amplitudes in both VIP and non-VIP SCN neurons, consistent with rhythmic changes in ionic conductances that contribute to shaping the firing properties of both cell types. The higher day and night firing rates of VIP neurons likely contribute to synchronizing electrical activity in the SCN.
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http://dx.doi.org/10.1177/0748730415619745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940538PMC
February 2016

Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling.

Trends Cardiovasc Med 2016 Apr 17;26(3):209-18. Epub 2015 Jul 17.

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO; Internal Medicine, Washington University School of Medicine, St. Louis, MO; Cardiovascular Division, Washington University School of Medicine, St. Louis, MO. Electronic address:

In the mammalian heart, multiple types of K(+) channels contribute to the control of cardiac electrical and mechanical functioning through the regulation of resting membrane potentials, action potential waveforms and refractoriness. There are similarly vast arrays of K(+) channel pore-forming and accessory subunits that contribute to the generation of functional myocardial K(+) channel diversity. Maladaptive remodeling of K(+) channels associated with cardiac and systemic diseases results in impaired repolarization and increased propensity for arrhythmias. Here, we review the diverse transcriptional, post-transcriptional, post-translational, and epigenetic mechanisms contributing to regulating the expression, distribution, and remodeling of cardiac K(+) channels under physiological and pathological conditions.
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http://dx.doi.org/10.1016/j.tcm.2015.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715991PMC
April 2016

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Circadian Period of PER2 Expression in the Suprachiasmatic Nucleus.

J Biol Rhythms 2015 Oct 6;30(5):396-407. Epub 2015 Jul 6.

Department of Biology, Washington University, St. Louis, MO, USA.

Neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, display daily rhythms in electrical activity with more depolarized resting potentials and higher firing rates during the day than at night. Although these daily variations in the electrical properties of SCN neurons are required for circadian rhythms in physiology and behavior, the mechanisms linking changes in neuronal excitability to the molecular clock are not known. Recently, we reported that mice deficient for either Kcna4 (Kv1.4(-/-)) or Kcnd2 (Kv4.2(-/-); but not Kcnd3, Kv4.3(-/-)), voltage-gated K(+) (Kv) channel pore-forming subunits that encode subthreshold, rapidly activating, and inactivating K(+) currents (IA), have shortened (0.5 h) circadian periods in SCN firing and in locomotor activity compared with wild-type (WT) mice. In the experiments here, we used a mouse (Per2(Luc)) line engineered with a bioluminescent reporter construct, PERIOD2::LUCIFERASE (PER2::LUC), replacing the endogenous Per2 locus, to test the hypothesis that the loss of Kv1.4- or Kv4.2-encoded IA channels also modifies circadian rhythms in the expression of the clock protein PERIOD2 (PER2). We found that SCN explants from Kv1.4(-/-)Per2(Luc) and Kv4.2(-/-) Per2(Luc), but not Kv4.3(-/-)Per2(Luc), mice have significantly shorter (by approximately 0.5 h) circadian periods in PER2 rhythms, compared with explants from Per2(Luc) mice, revealing that the membrane properties of SCN neurons feedback to regulate clock (PER2) expression. The combined loss of both Kv1.4- and Kv4.2-encoded IA channels in Kv1.4(-/-)/Kv4.2(-/-)Per2(Luc) SCN explants did not result in any further alterations in PER2 rhythms. Interestingly, however, mice lacking both Kv1.4 and Kv4.2 show a striking (approximately 1.8 h) advance in their daily activity onset in a light cycle compared with WT mice, suggesting additional roles for Kv1.4- and Kv4.2-encoded IA channels in controlling the light-dependent responses of neurons within and/or outside of the SCN to regulate circadian phase of daily activity.
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http://dx.doi.org/10.1177/0748730415593377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939214PMC
October 2015
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