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Calcium signaling in the heart: Role of SR Ca2+ release channels (RyRs) in health and disease

English title Calcium signaling in the heart: Role of SR Ca2+ release channels (RyRs) in health and disease
Applicant Niggli Ernst
Number 132689
Funding scheme Project funding (Div. I-III)
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.10.2010 - 30.09.2014
Approved amount 629'622.00
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Keywords (9)

Heart; calcium signals; heart failure; dystrophic cardiomyopathy; mutations; Cardiac muscle; Calcium signaling; Ryanodine receptors; CaMKII

Lay Summary (German)

Lead
Bei vielen Herzkrankheiten führt eine Beinträchtigung der zellulären Kalziumsignale zu einer Schwächung des Herzmuskels. In diesem Projekt wird die Funktion der Proteine, welche diese Signale kontrollieren, untersucht. Das Verständnis von pathologischen Funktionsänderungen dieser Proteine wird die Entwicklung neuer Therapiekonzepte ermöglichen.
Lay summary

Hintergrund:

Seit geraumer Zeit ist bekannt, dass die Funktion des Kalziumsingnalsystems der Herzmuskelzellen bei vielen Krankheiten gestört ist. Dieser Umstand ist für die inadaequate Herzmuskelkraft in solchen Situationen verantwortlich. Jede Herzmuskelzelle besitzt einen eingebauten “Verstärker” für Kalziumsignale, bestehend aus einer Organelle mit Speicherfunktion für Kalzium (das sarkoplasmatische Retikulum), Kanalproteinen zur Kalziumfreisetzung, und sogenannte Kalziumpumpen zum Wiederauffüllen des Speichers. Krankheitsbedingte Veränderungen der Funktion der Kanalproteine, auch Ryanodinrezeptoren genannt, stehen im Zentrum dieses Projekts, da diese zu Herzmuskelschwäche und Herzrhythmusstörungen führen können.

Ziel:

In diesem Projekt untersuchen wir Funktionsänderungen dieses Kanals, wie sie im Rahmen verschiedener physiologischer regulatorischer Vorgänge und bei Erkrankungen auftreten können, mit biophysikalischen und bildgebenden Methoden an isolierten Herzmuskelzellen. Wir testen die Hypothese, dass ganz verschiedene Störungen letzten Endes ganz ähnliche Funktionsänderungen dieser Kanäle bewirken. Zu den Störungen gehören zum Beispiel Funktionsänderungen infolge von Stress, aber auch bekannte Mutationen in diesem Kanal und Erbkrankheiten wie die Muskeldystrophie.

Bedeutung:

Erkrankungen des Herz-Kreislaufsystems sind nach wie vor die wichtigtes Todesursache in allen Industrienationen. Die Herzmuskelschwächen sind leider immer noch nicht adäquat behandelbar, aber deren Häufigkeit nimmt in der alternden Bevölkerung stetig zu und wird endemische Proportionen annehmen. Ein verbessertes Verständnis der zugrunde liegenden Pathomechanismen wird für die zukünftige Entwicklung neuer Behandlungsmethoden von zentraler Bedeutung sein.

 

Direct link to Lay Summary Last update: 29.09.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Calcium Uncaging with Visible Light.
Agarwal Hitesh, Janicek Radoslav, Chi San-Hui, Perry Joseph, Niggli Ernst, Ellis-Davies Graham CR (2016), Calcium Uncaging with Visible Light., in JACS, 138, 3687-3693.
Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression
Plaisance Isabelle, Perruchoud St{é}}phanie, Fernandez-Tenorio Miguel, Gonzales Christine, Ounzain Samir, Ruchat Patrick, Nemir Mohamed, Niggli Ernst, Pedrazzini Thierry (2016), Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression, in {JACC}: Basic to Translational Science, 1(6), 472-493.
Real-time intra-store confocal Ca2+ imaging in isolated mouse cardiomyocytes
Fernandez-Tenorio Miguel, Niggli Ernst (2016), Real-time intra-store confocal Ca2+ imaging in isolated mouse cardiomyocytes, in Cell Calcium, 60(5), 331-340.
Dystrophic cardiomyopathy: role of TRPV2 channels in stretch-induced cell damage
Lorin C., Vogeli I., Niggli E. (2015), Dystrophic cardiomyopathy: role of TRPV2 channels in stretch-induced cell damage, in Cardiovascular Research, 106, 153-162.
IP3 and Ca(2+) signals in the heart: boost them or bust them?
Niggli Ernst (2015), IP3 and Ca(2+) signals in the heart: boost them or bust them?, in J Physiol, 593, 1385-1386.
Cardiac phenotype of Duchenne Muscular Dystrophy: Insights from cellular studies.
Shirokova Natalia, Niggli Ernst (2013), Cardiac phenotype of Duchenne Muscular Dystrophy: Insights from cellular studies., in Journal of molecular and cellular cardiology, 58, 217-24.
Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy.
Kyrychenko Sergii, Poláková Eva, Kang Chifei, Pocsai Krisztina, Ullrich Nina D, Niggli Ernst, Shirokova Natalia (2013), Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy., in Cardiovascular research, 97(4), 666-75.
NO-dependent CaMKII activation during β-adrenergic stimulation of cardiac muscle.
Gutierrez Daniel A, Fernandez-Tenorio Miguel, Ogrodnik Jakob, Niggli Ernst (2013), NO-dependent CaMKII activation during β-adrenergic stimulation of cardiac muscle., in Cardiovascular research, 100(3), 392-401.
Posttranslational modifications of cardiac ryanodine receptors: Ca(2+) signaling and EC-coupling.
Niggli Ernst, Ullrich Nina D, Gutierrez Daniel, Kyrychenko Sergii, Poláková Eva, Shirokova Natalia (2013), Posttranslational modifications of cardiac ryanodine receptors: Ca(2+) signaling and EC-coupling., in Biochimica et biophysica acta, 1833(4), 866-75.
PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity.
Ullrich Nina D, Valdivia Héctor H, Niggli Ernst (2012), PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity., in Journal of molecular and cellular cardiology, 53(1), 33-42.
Alterations of excitation-contraction coupling and excitation coupled Ca(2+) entry in human myotubes carrying CAV3 mutations linked to rippling muscle.
Ullrich Nina D, Fischer Dirk, Kornblum Cornelia, Walter Maggie C, Niggli Ernst, Zorzato Francesco, Treves Susan (2011), Alterations of excitation-contraction coupling and excitation coupled Ca(2+) entry in human myotubes carrying CAV3 mutations linked to rippling muscle., in Human mutation, 32(3), 309-17.
Isolation of Cardiovascular Precursor Cells from the Human Fetal Heart.
Gonzales Christine, Ullrich Nina D, Gerber Stefan, Berthonneche Corinne, Niggli Ernst, Pedrazzini Thierry (2011), Isolation of Cardiovascular Precursor Cells from the Human Fetal Heart., in Tissue engineering. Part A, 18, 192-207.
Measuring calcium in 'fuzzy' spaces.
Niggli Ernst (2011), Measuring calcium in 'fuzzy' spaces., in The Journal of physiology, 589(Pt 11), 2663-2663.
Pathways of abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes
Fanchaouy M, Polakova E, Jung C, Ogrodnik J, Shirokova N, Niggli E (2011), Pathways of abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes, in CELL CALCIUM, 46(2), 114-121.
Ryanodine receptors: waking up from refractoriness.
Niggli Ernst (2011), Ryanodine receptors: waking up from refractoriness., in Cardiovascular research, 91(4), 563-4.
Increased Ca(2+) leak and spatiotemporal coherence of Ca(2+) release in cardiomyocytes during beta-adrenergic stimulation.
Ogrodnik Jakob, Niggli Ernst (2010), Increased Ca(2+) leak and spatiotemporal coherence of Ca(2+) release in cardiomyocytes during beta-adrenergic stimulation., in The Journal of physiology, 588(Pt 1), 225-42.
Maximal acceleration of calcium release refractoriness by β-adrenergic stimulation requires dual activation of protein kinase A and CaMKII in mouse ventricular myocytes.
Poláková Eva, Illaste Ardo, Niggli Ernst, Sobie Eric A, Maximal acceleration of calcium release refractoriness by β-adrenergic stimulation requires dual activation of protein kinase A and CaMKII in mouse ventricular myocytes., in The Journal of physiology.
Oxidative stress and Ca2+ release events in mouse cardiomyocytes
Shirokova Natalia, Kang Chifei, Fernandez Miguel, Wang Wei, Wang Qiongling, Wehrens Xander, Niggli Ernst, Oxidative stress and Ca2+ release events in mouse cardiomyocytes, in Biophysical Journal.

Collaboration

Group / person Country
Types of collaboration
H.Valdivia, UWisc, Madison WI United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
S. Treves, Uni Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
N.Shirokova, Rutgers University, Newark NJ United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
T. Pedrazzini, Uni Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
E. Sobie, Mount Sinai Hospital, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
A. Gomez, INSERM Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
X. Wehrens, Baylor College, Houston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gordon Conference - Cardiac Regulatory Mechanisms 2014 Talk given at a conference 1 talk: "Extraction of Detailed Ca2+ Signaling Information from Noisy Images" and 2 posters 08.06.2014 New London, NH, United States of America Illaste Ardo; Niggli Ernst;
Annual Meeting of the Heart Rhythm Society 2014 Talk given at a conference The Impact of Silvio Weidmann in the EP Community 08.05.2014 San Francisco, United States of America Niggli Ernst;
Seminar in Homburg Individual talk Manipulating Intracelluar Calcium with Light 18.04.2014 Homburg, Germany Niggli Ernst;
Seminar in Bern Individual talk Dystrophic Cardiomyopathy - Insight from Cellular Studies 13.03.2014 Bern, Cardiology, Switzerland Niggli Ernst;
Annual Meeting of the Biophysical Society 2014 Poster Two posters 20.02.2014 San Francisco, United States of America Niggli Ernst; Illaste Ardo;
AGLA & Cardiovascular Biology Meeting 2014 Poster Two posters 16.01.2014 Fribourg, Switzerland Niggli Ernst; Lorin Charlotte; Potenza Duilio Michele;
Seminar in Tallin Individual talk β-Adrenergic Stimulation: Protein Kinase Modulation of Cardiac RyRs 18.12.2013 Tallin, Estonia Niggli Ernst; Illaste Ardo;
Annual Meeting of the Biophysical Society 2013 Poster Three posters 15.02.2013 Philadelphia, United States of America Illaste Ardo; Niggli Ernst; Gutierrez Pineda Daniel Arturo;
AGLA & Cardiovascular Biology Meeting 2013 Poster Several posters: Direct CaMKII Activation by Endogenous Nitric Oxide Modulates Calcium Spark Frequency in Cardiomyocytes 10.01.2013 Bern, Switzerland Illaste Ardo; Niggli Ernst; Gutierrez Pineda Daniel Arturo;
Hans-Sigrist Symposium Talk given at a conference Probing and manipulating cellular signals with lasers 30.11.2012 Bern, Switzerland Niggli Ernst;
Annual Meeting of the Swiss Physiological Society 2012 Talk given at a conference In cardiac myocytes the elevation of Ca2+ spark frequency during beta-adrenergic stimulation depends on CaMKII and nitric oxide. 13.09.2012 Fribourg, Switzerland Niggli Ernst; Gutierrez Pineda Daniel Arturo;
Seminar in Heidelberg Individual talk Post-Translational Modifications of Cardiac RyRs: Ca signaling and EC-coupling 10.07.2012 Heidelberg, Physiology, Germany Niggli Ernst;
Gordon Conference - Cardiac Regulatory Mechanisms 2012 Poster PKA Phosphorylation of Cardiac Ryanodine Receptor Modulates SR Luminal Ca2+ Sensitivity 10.06.2012 New London NH / USA, United States of America Lorin Charlotte; Gutierrez Pineda Daniel Arturo; Niggli Ernst;
7th Ascona International Workshop on Cardiomyocyte Biology - Invited speaker Talk given at a conference Post-translational modifications of cardiac RyRs: Ca2+ signaling and EC-coupling 22.04.2012 Ascona, Switzerland Niggli Ernst;
AGLA & Cardiovascular Biology Meeting 2012, Zürich Poster PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity 08.03.2012 Zürich, Switzerland Niggli Ernst; Gutierrez Pineda Daniel Arturo;
Annual Meeting of the Biophysical Society 2012 Poster Several posters 25.02.2012 San Diego, United States of America Niggli Ernst; Gutierrez Pineda Daniel Arturo; Illaste Ardo;
Seminar Poitiers Individual talk Post-Translational Modifications of Cardiac RyRs and EC-coupling 02.12.2011 Poitiers, Physiology, France Niggli Ernst;
8th European Biophysics Congress - Session chair and invited speaker Talk given at a conference Alterations of ryanodine receptor (RyR) function and arrhythmogenic Ca2+ waves in cardiomyocytes 23.08.2011 Budapest, Hungary Niggli Ernst;
ISHR European Section Meeting 2011 - Invited speaker Talk given at a conference Remodeling of cardiomyocyte excitation-contraction coupling 26.06.2011 Haifa / Israel, Israel Niggli Ernst;
Seminar in Göttingen Individual talk Post-Translational Modifications of Cardiac RyRs and EC-coupling 14.04.2011 Göttingen, Cardiology, Germany Niggli Ernst;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Interview zum Thema "Hitzewelle" Radio DRS Western Switzerland 2012

Awards

Title Year
Poster prize - AGLA meeting Bern 2013
Poster prize - AGLA meeting Zurich 2012
Young Investigator award - Swiss Physiological Society 2012

Associated projects

Number Title Start Funding scheme
109693 Regulation and Remodeling of Calcium Signaling and Excitation-Contraction Coupling in Cardiac Muscle 01.10.2005 Project funding (Div. I-III)
139231 Advancement of functional genomics research at the University of Bern by extension of LC-MS platform 01.07.2012 R'EQUIP
156375 Cardiac calcium signaling in health and disease: role of SR Ca2+ release and ryanodine receptor release channels (RyRs) 01.10.2014 Project funding (Div. I-III)

Abstract

1.1. Background and rationale:In cardiac muscle contraction is activated by transient elevations of the intracellular Ca2+ concentration ([Ca2+]i). The mechanisms governing these Ca2+ signals are referred to as excitation-contraction (EC) coupling. A small amount of Ca2+ entering the cardiomyocytes via voltage-dependent Ca2+ channels is amplified several-fold by the mechanism of Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) via Ca2+ release channels (called ryanodine receptors or RyRs). The RyRs are thus the gatekeepers of EC-coupling. They form huge tetrameric macromolecular complexes with many associated proteins that have a regulatory and modulatory function. In addition, opening and closing of the RyRs is modulated by a variety of post-translational modifications, and by a multitude of cellular constituents and ions, all of which converge in their action on the RyRs and eventually impinge on this protein. Because of the resulting complexity, we will concentrate our experimental efforts on only four parameters associated with Ca2+ signaling and RyR function, carefully selected because of their importance in physiological regulation of cardiac muscle activity, but also to because of their pathophysiological impact relevant in specific diseases. The following mechanisms will be considered: 1) regulation of RyR activity by ß-adrenergic receptor (ß-AR) stimulation and phosphorylation. 2) redox modifications of the RyRs by reactive oxygen (and nitrogen) species. 3) destabilization of the RyR resulting from a RyR mutation. 4) changes of RyR Ca2+ sensitivity by the intra-SR luminal Ca2+ concentration. To characterize how these 4 mechanisms shape RyR function, cardiac Ca2+ signaling and EC-coupling, either by mutually exclusive or synergistic interactions, is the overarching goal of this project. 1.2. Working hypothesis:We propose the hypothesis that in a living cardiac muscle cells each of the four mechanisms mentioned above can independently affect the Ca2+ sensitivity of the RyRs and ultimately modify the gating of these channels. This also implies the testable hypothesis that the mechanisms contribute synergistically (and additively) to the functional state of the RyR macromolecular complex. 1.3. General aims:In this project we will follow four aims (1 and 2A-C), logically linked by their common mechanism to modulate the function of the RyRs. 1) We will assess how RyR function is modified by ß-AR stimulation, possibly involving RyR phosphorylation. This will involve studies on the RyR activity at rest (i.e. between heartbeats) and during triggered Ca2+ release events (i.e. during systole). 2A) We will examine, with a similar experimental aproach, how changes in redox environment, associated with several cardiomyopathies, alter RyR channel function. 2B) We will elucidate how destabilizing and arrhythmogenic RyR mutations found in patients interfere with EC-coupling and Ca2+ signaling. 2C) We will investigate by which mechanisms the Ca2+ concentration in the SR affects RyR Ca2+ sensitivity leading to arrhythmogenic Ca2+ waves, with particular attention to “tandem wave” mechanisms.1.4. Experimental design and methods:Confocal imaging of Ca2+ signals in isolated cardiomyocytes loaded with fluorescent indicators will be combined with the cellular electrophysiology techniques (patch-clamp) and photolysis of caged compounds (UV-laser flash or two-photon excitation). Intact, but also permeabilized myocytes from guinea-pigs and mice are chosen for the proposed studies. Two transgenic animals with minimal phenotype in control conditions will help us to identify and characterize some important steps of the signaling mechanisms relevant for stress and RyR mutations. One transgenic mouse has a RyR that cannot be phosphorylated at a specific serine residue, while the second animal model harbors a destabilizing and arrhythmogenic RyR mutation previously identified in humans. To derive information about the RyR function under specific conditions, we will analyze Ca2+ spark parameters (e.g. frequency, amplitude), quantify the degree of synchronization of triggered Ca2+ transients, which is a sensitive indicator of reliable and coordinated RyR gating. We will also analyze the reliability of the signal transduction from the L-type Ca2+ channels to the RyRs by assaying macroscopic and microscopic EC-coupling gain functions.1.5. Expected value of the proposed project:With the proposed experiments we expect to obtain new information about fundamental cellular and molecular mechanisms that enable the heart to regulate the produced force and how this regulation may be impaired in cardiac diseases. The RyRs are now considered a promising drug target and a new class of pharmacological compounds stabilizing the RyRs (so called “Rycals”) are under development. Thus, besides our genuine interest to comprehend the functioning of cardiac Ca2+ release and EC-coupling, a detailed mechanistic and pathomechanistic understanding of the RyRs is of crucial importance. With the present study we hope to contribute key information about some of these important mechanisms and how they interact synergistically or deleteriously by their ability to change RyR function in favorable or harmful ways.
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