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203. Na+ channel function, regulation, structure, trafficking and sequestration

Author

Abriel, Hugues, Izu, Leighton T, Marionneau, Celine, Sack, Jon T, Yarov-Yarovoy, Vladimir, Pitt, Geoffrey S, Shaw, Robin M, Chiamvimonvat, Nipavan, Cannell, Mark B, Catterall, William A, Chen-Izu, Ye, Aldrich, Richard W, Chazin, Walter J, Mohler, Peter J, Rajamani, Sridharan, Bers, Donald M, Maier, Lars S, Hund, Thomas J, Clancy, Colleen E, Grandi, Eleonora, Maltsev, Victor A, Sobie, Eric A, Rasmusson, Randall L, Belardinelli, Luiz, and Deschenes, Isabelle

Subjects
Myocytes, Life on Land, Physiology, Molecular Sequence Data, Action Potentials, Congresses as Topic, Biological Sciences, Cardiovascular, Medical and Health Sciences, White Papers, Sodium Channels, Protein Transport, Heart Disease, Animals, Humans, Myocytes, Cardiac, Amino Acid Sequence, 610 Medicine & health, Cardiac, Sodium Channel Blockers
Abstract

This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) channel and Na(+) transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na(+) channel function and regulation, Na(+) channel structure and function, and Na(+) channel trafficking, sequestration and complexing.

Published
2015

204. Molecular identification of a TTX-sensitive [Ca.sup.2+] current

Author

GUATIMOSIM, SILVIA, SOBIE, ERIC A., CRUZ, JADER DOS SANTOS, MARTIN, LAURA A., and LEDERER, W. J.

Subjects
Muscle cells -- Analysis, Calcium channels -- Genetic aspects, Tetrodotoxin -- Genetic aspects, Sodium channels -- Genetic aspects, Biological sciences
Abstract

Molecular identification of a TTX-sensitive [Ca.sup.2+] current. Am J Physiol Cell Physiol 280: C1327-C1339, 2001.--The TTX-sensitive [Ca.sup.2+] current [[I.sub.Ca(TTX)]] observed in cardiac myocytes under [Na.sup.+]-free conditions was investigated using patch-clamp and [Ca.sup.2+]-imaging methods. [Cs.sup.+] and [Ca.sup.2+] were found to contribute to [I.sub.Ca(TTX)], but [TEA.sup.+] and N-methyl-D-glucamine ([NMDG.sup.+]) did not. HEK-293 cells transfected with cardiac [Na.sup.+] channels exhibited a current that resembled [I.sub.Ca(TTX)] in cardiac myocytes with regard to voltage dependence, inactivation kinetics, and ion selectivity, suggesting that the cardiac [Na.sup.+] channel itself gives rise to [I.sub.Ca(TTX)]. Furthermore, repeated activation of [I.sub.Ca(TTX)] led to a 60% increase in intracellular [Ca.sup.2+] concentration, confirming [Ca.sup.2+] entry through this current. [Ba.sup.2+] permeation of [I.sub.Ca(TTX)], reported by others, did not occur in rat myocytes or in HEK-293 cells expressing cardiac [Na.sup.+] channels under our experimental conditions. The report of block of [I.sub.Ca(TTX)] in guinea pig heart by mibefradil (10 [micro]M) was supported in transfected HEK-293 cells, but [Na.sup.+] current was also blocked (half-block at 0.45 [micro]M). We conclude that [I.sub.Ca(TTX)] reflects current through cardiac [Na.sup.+] channels in [Na.sup.+]-free (or 'null') conditions. We suggest that the current be renamed [I.sub.Na(null)] to more accurately reflect the molecular identity of the channel and the conditions needed for its activation. The relationship between [I.sub.Na(null)] and [Ca.sup.2+] flux through slip-mode conductance of cardiac [Na.sup.+] channels is discussed in the context of ion channel biophysics and 'permeation plasticity.' tetrodotoxin; excitation-contraction coupling; sodium channel; calcium channel; ventricular myocyte

Published
2001

219. Na+ channel function, regulation, structure, trafficking and sequestration.

Author

Chen-Izu, Ye, Chen-Izu, Ye, Shaw, Robin M, Pitt, Geoffrey S, Yarov-Yarovoy, Vladimir, Sack, Jon T, Abriel, Hugues, Aldrich, Richard W, Belardinelli, Luiz, Cannell, Mark B, Catterall, William A, Chazin, Walter J, Chiamvimonvat, Nipavan, Deschenes, Isabelle, Grandi, Eleonora, Hund, Thomas J, Izu, Leighton T, Maier, Lars S, Maltsev, Victor A, Marionneau, Celine, Mohler, Peter J, Rajamani, Sridharan, Rasmusson, Randall L, Sobie, Eric A, Clancy, Colleen E, Bers, Donald M, Chen-Izu, Ye, Chen-Izu, Ye, Shaw, Robin M, Pitt, Geoffrey S, Yarov-Yarovoy, Vladimir, Sack, Jon T, Abriel, Hugues, Aldrich, Richard W, Belardinelli, Luiz, Cannell, Mark B, Catterall, William A, Chazin, Walter J, Chiamvimonvat, Nipavan, Deschenes, Isabelle, Grandi, Eleonora, Hund, Thomas J, Izu, Leighton T, Maier, Lars S, Maltsev, Victor A, Marionneau, Celine, Mohler, Peter J, Rajamani, Sridharan, Rasmusson, Randall L, Sobie, Eric A, Clancy, Colleen E, and Bers, Donald M

Abstract

This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) channel and Na(+) transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na(+) channel function and regulation, Na(+) channel structure and function, and Na(+) channel trafficking, sequestration and complexing.

Published
2015

220. Pharmacometrics and Systems Pharmacology 2030.

Author

Mentré, France, Friberg, Lena E., Duffull, Stephen, French, Jonathan, Lauffenburger, Douglas A., Li, Lang, Mager, Donald E., Sinha, Vikram, Sobie, Eric, and Zhao, Ping

Subjects
PHARMACOLOGY, DRUG development
Abstract

In 2012, a new journal was launched from the ASCPT family, CPT: Pharmacometrics and Systems Pharmacology (PSP) as both quantitative system pharmacology (QSP) and pharmacometrics were growing fields in pharmacology, drug development, and drug use. In this Perspective, the present editors and associate editors of PSP want to share their strategic vision of where these two fields, separately and together, should, would, or could be 10 years from now. [ABSTRACT FROM AUTHOR]

Published
2020
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221. Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations.

Author

Mora, Maria T., Ferrero, Jose M., Gomez, Juan F., Sobie, Eric A., and Trenor, Beatriz

Subjects
HEART failure, MUSCLE cells, FIBROBLASTS, CELL proliferation, CYCLING
Abstract

Heart failure (HF) is characterized by altered Ca2+ cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca2+ homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca2+ cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte–fibroblast coupling could affect Ca2+ dynamics in normal conditions and in HF. Simulations of healthy and failing human myocytes were performed using established mathematical models, and cells were either isolated or coupled to fibroblasts. Univariate and multivariate sensitivity analyses were performed to quantify effects of ion transport pathways on biomarkers computed from intracellular [Ca2+] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca2+ dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca2+ impairment in HF, although differences between the two methodologies are observed at high parameter variability. These can result from either the fact that multivariate analyses take into account ion channels or non-linear effects of ion transport pathways on Ca2+ dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca2+ transients due to an indirect sink effect on action potential (AP) and thus on Ca2+ related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca2+ cycling can be normalized by increasing SERCA and L-type Ca2+ current activity while decreasing Na+–Ca2+ exchange and SR Ca2+ leak. Changes required to normalize APs in failing myocytes depended on whether myocytes were coupled to fibroblasts. In conclusion, univariate and multivariate sensitivity analyses are helpful tools to understand how Ca2+ cycling is impaired in HF and how this can be exacerbated by coupling of myocytes to fibroblasts. The design of pharmacological actions to restore normal activity should take into account the degree of fibrosis in the failing heart. [ABSTRACT FROM AUTHOR]

Published
2018
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222. Pathogenesis of the Novel Autoimmune-Associated Long-QT Syndrome

Author

Yue, Yuankun, primary, Castrichini, Monica, additional, Srivastava, Ujala, additional, Fabris, Frank, additional, Shah, Krupa, additional, Li, Zhiqiang, additional, Qu, Yongxia, additional, El-Sherif, Nabil, additional, Zhou, Zhengfeng, additional, January, Craig, additional, Hussain, M. Mahmood, additional, Jiang, Xian-Cheng, additional, Sobie, Eric A., additional, Wahren-Herlenius, Marie, additional, Chahine, Mohamed, additional, Capecchi, Pier-Leopoldo, additional, Laghi-Pasini, Franco, additional, Lazzerini, Pietro-Enea, additional, and Boutjdir, Mohamed, additional

Published
2015
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223. Na+ channel function, regulation, structure, trafficking and sequestration

Author

Chen‐Izu, Ye, primary, Shaw, Robin M., additional, Pitt, Geoffrey S., additional, Yarov‐Yarovoy, Vladimir, additional, Sack, Jon T., additional, Abriel, Hugues, additional, Aldrich, Richard W., additional, Belardinelli, Luiz, additional, Cannell, Mark B., additional, Catterall, William A., additional, Chazin, Walter J., additional, Chiamvimonvat, Nipavan, additional, Deschenes, Isabelle, additional, Grandi, Eleonora, additional, Hund, Thomas J., additional, Izu, Leighton T., additional, Maier, Lars S., additional, Maltsev, Victor A., additional, Marionneau, Celine, additional, Mohler, Peter J., additional, Rajamani, Sridharan, additional, Rasmusson, Randall L., additional, Sobie, Eric A., additional, Clancy, Colleen E., additional, and Bers, Donald M., additional

Published
2015
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227. Excitation–contraction coupling gain in ventricular myocytes: insights from a parsimonious model

Author

Sobie, Eric A and Ramay, Hena R

Subjects
Patch-Clamp Techniques, Calcium Channels, L-Type, Animals, Humans, Computer Simulation, Myocytes, Cardiac, Calcium Signaling, Cardiovascular, Ion Channel Gating, Models, Biological, Algorithms, Membrane Potentials, Muscle Contraction
Abstract

We present a minimal mathematical model of Ca(2+) spark triggering under voltage-clamp conditions in ventricular myocytes. The model predicts changes in excitation-contraction coupling 'gain' that result from diverse experimental interventions. We compare model results to several sets of data, and, in so doing, place apparent constraints on physiologically relevant model parameters. Specifically, the analysis suggests that many L-type Ca(2+) channel openings can potentially trigger each Ca(2+) spark, but the probability that an individual opening will trigger a spark is low. This procedure helps to reconcile contradictory results obtained in recent studies; moreover, this new model should be a useful tool for understanding changes in gain that occur physiologically and in disease.

Published
2009

229. Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

Author

Devenyi, Ryan A., Ortega, Francis A., Groenendaal, Willemijn, Krogh‐Madsen, Trine, Christini, David J., and Sobie, Eric A.

Subjects
ARRHYTHMIA, HEART cells, GUINEA pigs, MATHEMATICAL models, MORPHOLOGY
Abstract

Key points Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood., We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated., A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model., The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias., Abstract Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K+ current and a drastic decrease in the slow delayed rectifier K+ current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K+ currents influences ventricular arrhythmia susceptibility. [ABSTRACT FROM AUTHOR]

Published
2017
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230. Local recovery of Ca2+ release in rat ventricular myocytes

Author

Sobie, Eric A, Song, Long-Sheng, and Lederer, WJ

Subjects
Cell Physiology, Microscopy, Confocal, Heart Ventricles, cardiovascular system, Reaction Time, Animals, Calcium, Myocytes, Cardiac, Calcium Signaling, Rats
Abstract

Excitation-contraction coupling in the heart depends on the positive feedback process of Ca2+-induced Ca2+ release (CICR). While CICR provides for robust triggering of Ca2+ sparks, the mechanisms underlying their termination remain unknown. At present, it is unclear how a cluster of Ca2+ release channels (ryanodine receptors or RyRs) can be made to turn off when their activity is sustained by the Ca2+ release itself. We use a novel experimental approach to investigate indirectly this issue by exploring restitution of Ca2+ sparks. We exploit the fact that ryanodine can bind, nearly irreversibly, to an RyR subunit (monomer) and increase the open probability of the homotetrameric channel. By applying low concentrations of ryanodine to rat ventricular myocytes, we observe repeated activations of individual Ca2+ spark sites. Examination of these repetitive Ca2+ sparks reveals that spark amplitude recovers with a time constant of 91 ms whereas the sigmoidal recovery of triggering probability lags behind amplitude recovery by approximately 80 ms. We conclude that restitution of Ca2+ sparks depends on local refilling of SR stores after depletion and may also depend on another time-dependent process such as recovery from inactivation or a slow conformational change after rebinding of Ca2+ to SR regulatory proteins.

Published
2005

235. Identification and Purification of Human Induced Pluripotent Stem Cell-Derived Atrial-Like Cardiomyocytes Based on Sarcolipin Expression

Author

Josowitz, Rebecca, primary, Lu, Jia, additional, Falce, Christine, additional, D’Souza, Sunita L., additional, Wu, Meng, additional, Cohen, Ninette, additional, Dubois, Nicole C., additional, Zhao, Yong, additional, Sobie, Eric A., additional, Fishman, Glenn I., additional, and Gelb, Bruce D., additional

Published
2014
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241. The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations

Author

Keenan, Alexandra B., Jenkins, Sherry L., Jagodnik, Kathleen M., Koplev, Simon, He, Edward, Torre, Denis, Wang, Zichen, Dohlman, Anders B., Silverstein, Moshe C., Lachmann, Alexander, Kuleshov, Maxim V., Ma'ayan, Avi, Stathias, Vasileios, Terryn, Raymond, Cooper, Daniel, Forlin, Michele, Koleti, Amar, Vidovic, Dusica, Chung, Caty, Schürer, Stephan C., Vasiliauskas, Jouzas, Pilarczyk, Marcin, Shamsaei, Behrouz, Fazel, Mehdi, Ren, Yan, Niu, Wen, Clark, Nicholas A., White, Shana, Mahi, Naim, Zhang, Lixia, Kouril, Michal, Reichard, John F., Sivaganesan, Siva, Medvedovic, Mario, Meller, Jaroslaw, Koch, Rick J., Birtwistle, Marc R., Iyengar, Ravi, Sobie, Eric A., Azeloglu, Evren U., Kaye, Julia, Osterloh, Jeannette, Haston, Kelly, Kalra, Jaslin, Finkbiener, Steve, Li, Jonathan, Milani, Pamela, Adam, Miriam, Escalante-Chong, Renan, Sachs, Karen, Lenail, Alex, Ramamoorthy, Divya, Fraenkel, Ernest, Daigle, Gavin, Hussain, Uzma, Coye, Alyssa, Rothstein, Jeffrey, Sareen, Dhruv, Ornelas, Loren, Banuelos, Maria, Mandefro, Berhan, Ho, Ritchie, Svendsen, Clive N., Lim, Ryan G., Stocksdale, Jennifer, Casale, Malcolm S., Thompson, Terri G., Wu, Jie, Thompson, Leslie M., Dardov, Victoria, Venkatraman, Vidya, Matlock, Andrea, Van Eyk, Jennifer E., Jaffe, Jacob D., Papanastasiou, Malvina, Subramanian, Aravind, Golub, Todd R., Erickson, Sean D., Fallahi-Sichani, Mohammad, Hafner, Marc, Gray, Nathanael S., Lin, Jia-Ren, Mills, Caitlin E., Muhlich, Jeremy L., Niepel, Mario, Shamu, Caroline E., Williams, Elizabeth H., Wrobel, David, Sorger, Peter K., Heiser, Laura M., Gray, Joe W., Korkola, James E., Mills, Gordon B., LaBarge, Mark, Feiler, Heidi S., Dane, Mark A., Bucher, Elmar, Nederlof, Michel, Sudar, Damir, Gross, Sean, Kilburn, David F., Smith, Rebecca, Devlin, Kaylyn, Margolis, Ron, Derr, Leslie, Lee, Albert, and Pillai, Ajay

Abstract

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.

Published
2018
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