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Inositol(1,4,5)-Triphosphate Signaling in Cardiomyocytes - Contribution to CICR

English title Inositol(1,4,5)-Triphosphate Signaling in Cardiomyocytes - Contribution to CICR
Applicant Egger Marcel
Number 149301
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 01.04.2014 - 31.03.2019
Approved amount 367'000.00
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Keywords (6)

Cardiac muscle; EC-coupling; Ca2+ signaling; InsP3; Atrial myocytes; CICR

Lay Summary (German)

Lead
Viele Details des zellulären Schlüsselmechanismus der Herzmuskel-Kontraktion, der Kalzium-induzierten Kalzium (CICR) Freisetzung sind bekannt. Details eines zweiten, Kalzium-Freisetzungs-Mechanismus in Herzmuskelzellen, der über das Signalmolekül Inositol-1,4,5-triphosphate aktiviert wird, sind nicht gut verstanden. Dieser scheint eine wichtige Rolle bei der zellulären Regulation der Kalzium Bereitstellung und bei zellulären Anpassungsprozessen in pathophysiologischen Situationen zu spielen.
Lay summary

In diesem Projekt ist es unser Ziel, den Mechanismus der Inositol-1,4,5-triphosphate aktivierten Kalzium-Freisetzung (IP3ICR) in Herzmuskelzellen besser zu verstehen. Wir werden intrazelluläre Kalzium-Freisetzungsereignisse in Vorhof-Myozyten und ventrikulären Myozyten im Detail bei unterschiedlichen intrazellulären Bedingungen und in verschiedenen Herz-Krankheitsmodellen untersuchen. Dazu werden wir mehrere biophysikalische Methoden miteinander kombinieren und simultan anwenden (Elektrophysiologie, Konfokale-Laser-Mikroskopie, intrazelluläre photolytische Freisetzung von Signalmolekülen u.a.). Im Besonderen möchten wir 1) die Rolle der IP3ICR für den CICR Mechanismus und deren Regulation durch intrazelluläre Signalwege und 2) pathophysiologische Veränderungen ("remodeling") des IP3ICR untersuchen. Dieses Projekt wird neue Erkenntnisse über die Interaktion von CICR und IP3ICR liefern, welche für das Verständnis von kalzium-abhängigen Herz-Arrhythmien von Bedeutung sind. Der im IP3ICR Mechanismus beteiligte Kalzium-Freisetzungskanal könnte ein potentielles „antiarrhythmic drug- target”  sein.


Direct link to Lay Summary Last update: 11.10.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Automatic Detection and Classification of Ca2+ Release Events in Line- and Frame-Scan Images
Illaste Ardo, Wullschleger Marcel, Fernandez-Tenorio Miguel, Niggli Ernst, Egger Marcel (2019), Automatic Detection and Classification of Ca2+ Release Events in Line- and Frame-Scan Images, in Biophysical Journal, 116(3), 383-394.
Obstruction of ventricular Ca2+‐dependent arrhythmogenicity by inositol 1,4,5‐trisphosphate‐triggered sarcoplasmic reticulum Ca2+ release
BlanchJoaquim, EggerMarcel (2018), Obstruction of ventricular Ca2+‐dependent arrhythmogenicity by inositol 1,4,5‐trisphosphate‐triggered sarcoplasmic reticulum Ca2+ release, in Journal of Physiology, 596(18), 4323-4340.
IP3-Induced SR-Ca2+ Release Functions as an Anti-arrhythmogenic Mechanism in Ventricular Myocytes
Blanch Salvador Joaquim, Egger Marcel (2018), IP3-Induced SR-Ca2+ Release Functions as an Anti-arrhythmogenic Mechanism in Ventricular Myocytes, in Biophysical Journal, 114(3), 213a-213a.
Functional local crosstalk of inositol 1,4,5-trisphosphate receptor- and ryanodine receptor-dependent Ca2+ release in atrial cardiomyocytes.
WullschlegerMarcel, BlanchJoaquim, EggerMarcel (2017), Functional local crosstalk of inositol 1,4,5-trisphosphate receptor- and ryanodine receptor-dependent Ca2+ release in atrial cardiomyocytes., in Cardiovascular research, (113), 542-552.
Cardiac Specific IP 3 R Over-Expression: IP3ICR Contribution in Ca 2+ Signaling
Blanch i Salvador Joaquim, Wullschleger Marcel, Egger Marcel (2017), Cardiac Specific IP 3 R Over-Expression: IP3ICR Contribution in Ca 2+ Signaling, in Biophysical Journal, 112(3), 540a-540a.

Collaboration

Group / person Country
Types of collaboration
Prof. H. Valdivia, University of Michigan United States of America (North America)
- Research Infrastructure
CAF University of Lausanne, Prof. T. Pedrazzini Switzerland (Europe)
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Biophysical Soc. 62nd. Annual Meeting Talk given at a conference IP3-INDUCED SR-CA2+ RELEASE FUNCTIONS AS AN ANTI-ARRHYTHMOGENIC MECHANISM IN VENTRICULAR MYOCYTES. 17.02.2018 San Francisco, CA, USA, United States of America Blanch i Salvador Joaquim; Egger Marcel;
Gordon Research Conference / Muscle: Excitation-Contraction Coupling Talk given at a conference Local crosstalk of inositol 1,4,5-triphosphate receptor- & ryanodine receptor-dependent Ca2+ release in atrial myocytes 04.06.2017 Les Diablerets Conference Center in Les Diablerets , Switzerland Egger Marcel; Blanch i Salvador Joaquim;
Bioiphysical Soc. 61st. Annual Meeting Poster Inositol(1,4,5)-triphosohate Ca2+ Release in Cardiomyocytes 11.02.2017 New Orleans, Louisiana, USA, United States of America Blanch i Salvador Joaquim; Egger Marcel;
Gordon Research Conference / Cardiac Regulatory Mechanisms Talk given at a conference Interaction of Different Types of Elementary Ca2+ Signaling Events in Atrial Cardiomyocytes 05.06.2016 Colby-Sawyer College, New London NH, USA, United States of America Egger Marcel; Blanch i Salvador Joaquim;
International Society for Heart Research / ISHR XXII World Congress Talk given at a conference FFunctional crosstalk of RyR2 and InsP3R2 mediated SR-Ca2+ release in atrial cardiomyocytes 18.04.2016 Buenos Aires, Argentina Egger Marcel; Fernandez Tenorio Miguel;
Gordon Research Conference / Muscle: Ecxcitation-Contracion Coupling Poster Ca2+ “puffs” and Ca2+ sparks evoked by InsP3R2 activation in atrial cardiomyocytes 31.05.2015 Sunday River in Newry ME, USA, United States of America Egger Marcel;


Associated projects

Number Title Start Funding scheme
185211 Remodeling of the Inositol(1,4,5)-Triphosphate Ca2+ release Mechanism in Cardiomyocytes: Beneficial or Detrimental? 01.05.2019 Project funding (Div. I-III)

Abstract

Background: In the heart, Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is the key mechanism governing excitation-contraction coupling (ECC) responsible for force production. In atrial and ventricular myocytes, a second mechanism, Ca2+ release through channels sensitive to the intracellular second messenger inositol-1,4,5-triphosphate (InsP3), has been described (IP3ICR) which may be critical for regulation of CICR under pathophysiological conditions. However, cellular and molecular details of IP3ICR and its role in cardiac Ca2+ signaling under physiological and pathophysiological situations in cardiomyocytes still remain unclear.Working hypothesis: Our working hypothesis is based on on the well documented observations of Ca2+ mismanagement linked to the development of Ca2+ triggered cardiac arrhythmias. We predict a functional and modulatory role for IP3ICR in CICR, e.g. in the appearance and propagation of spontaneous or triggered Ca2+ events (e.g. Ca2+ waves) in atrial and ventricular myocytes. Augmented InsP3 receptor (InsP3R) expression and function may contribute to a variety of cardiac pathologies including cardiac arrhythmia. We suggest, that the SR-Ca2+ leak (e.g. via “eventless” IP3ICR) based on the InsP3R activity may act as a critical regulatory determinant of the CICR mechanism under physiological and pathophysiological situations. This new concept of cellular CICR regulation could be involved in the complex event cascade possibly leading to Ca2+- triggered arrhythmias. General aims: In this research proposal we will follow three aims: 1) to understand the regulatory function and significance of the “eventless” InsP3R Ca2+ leak for the appearance and propagation of CICR events; 2) we will explore phenotypic changes of IP3ICR in a model of hypertrophic cardiomyopathy (HCM) in which we will focus on IP3ICR for Ca2+ wave propagation specifically in ventricular myocytes; 3) to examine InsP3R Ca2+ leak alterations and subsequent arrhythmogenic SR-Ca2+ release in response to phosphorylation. The second aim is directly linked to pathological modifications of the mechanisms examined in the general aim 1.Experimental design and methods: To address this aims we will apply a combination of laser-scanning confocal microscopy (mainly of Ca2+ signaling), photolysis of caged compounds, and whole-cell voltage clamp techniques. State-of-the-art biophysical techniques will be simultaneously applied on individual isolated cardiomyocytes loaded with fluorescent indicators or alternatively in permeabilized cells. Functional data will be complemented with molecular data regarding protein expression and immunohistochemistry of the InsP3R. In addition to pharmacological tools we will make use of two carefully selected transgenic mouse models: The InsP3R overexpressing mouse will help us to identify and to characterize the “invisible” IP3ICR, CICR crosstalk and to understand the role of IP3ICR in intracellular Ca2+ event propagation. A newly developed transgenic mouse model of hypertrophic cardiomyopathy (HCM, RyR2-P1124L mutation) will help to elucidate a possible contribution of IP3ICR in the total SR-Ca2+ leak which may be critical for development of hypertrophic cardiomyopathy. Overall cardiac phenotype will be assessed by non-invasive monitoring of mechanical and electrical parameters of cardiac function (ECG and echocardiography). To obtain informations about InsP3R function we will analyze Ca2+ event parameters and propagation of local Ca2+ events (Ca2+ sparks, Ca2+ puffs), SR-Ca2+ leak and changes in the luminal Ca2+. Together, the latter approaches will allow us to obtain detailed new information about the involved InsP3R regulatory mechanisms at the sub-cellular level in cardiomyocytes.Expected impact of the proposed project: The research proposal focusses on physiological and pathophysiological regulatory mechanisms of IP3ICR occurring on a cellular level in cardiac myocytes. Although cardiac arrhythmogenesis cannot be studied on single cell preparations, cellular regulatory mechanisms which could end up in these types of cardiac dysfunction can be examined. In essence, there will be two types of information gained from his study. First, we expect to obtain new information about the cellular and subcellular mechanisms involved in physiological and/or dysfunctional regulation of IP3ICR in cardiomyocytes. Second, dysfunction of Ca2+ homeostasis is known to feedback on electrical activity of cardiomyocytes. Therefore, our data will contribute to the understanding of cellular mechanisms linked to the development of Ca2+ triggered cardiac arrhythmias (e.g. HCM).
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