Cardiac excitation–contraction coupling: new developments

Over 100 years have elapsed since Sidney Ringer made the serendipitous discovery that calcium played a crucial role in amphibian cardiac contraction. Since then we have learned that this ion is an obligatory requirement for cardiac muscle of all species, and that the regulation of intracellular calcium levels is considerably more complex in the mammalian heart than previously thought. Part of this complexity is due to the involved design requirements of mammalian physiological processes. Another element of complexity is introduced by the quantitative differences in the involvement of various regulatory processes in different species. Finally, many significant technological advances in methods for investigating cardiac cellular functions have provided exciting experimental data. However, these data must be integrated into a unifying framework of knowledge of cardiac functions. Among the exciting recent developments are the use of a patch clamp technique to discover different kinds of calcium channels, a highly refined skinned fiber technique to study calcium-induced calcium release, and calcium indicator dyes and laser diffraction and scattering techniques to study the dynamics of calcium handling by the cell. These studies have not only provided clues about the normal functioning of the myocardial cell but have also reinforced the notion that altered function of the sarcoplasmic reticulum during intracellular calcium overload can influence sarcolemmal electrical function.This symposium, organized by the Pharmacological Society of Canada, examined some of the more recent technological advances in the field to provide a glimpse not only of the "state of the art" but also of future directions.This symposium was made possible by generous financial assistance from Boehringer Ingelheim (Canada) Ltd., Bristol-Myers Pharmaceutical Group, Canadian and Manitoba Heart Foundations, Ciba-Geigy Canada Ltd., Du Pont Canada Inc., Hoffmann LaRoche Ltd., Merck-Frosst Canada Inc., Miles Laboratories Inc., Nordic Laboratories Inc., Pfizer (Canada) Inc., Rhône-Poulenc Pharmaceuticals Inc., G. D. Searle of Canada, Ltd., Squibb Canada Inc., Sterling Drugs Ltd./Winthrop Laboratories, the Upjohn Company of Canada, and the University of Manitoba Pharmacology Department.

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Abstract MP135: Cardiac Sarcoplasmic Reticulum Calcium Cycling is Regulated by Kinase Independent Function of Pi3kgamma

Circulation Research ◽

10.1161/res.127.suppl_1.mp135 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Maradumane L Mohan ◽

Conner P Witherow ◽

Robert S Papay ◽

Sathyamangla V Naga Prasad

Keyword(s):

Intracellular Calcium ◽

Calcium Release ◽

Cardiac Contractility ◽

Underlying Mechanism ◽

Calcium Handling ◽

Ventricular Contractility ◽

Independent Function ◽

Calcium Cycling ◽

Cardiac Sarcoplasmic Reticulum ◽

Phosphoinositide 3 Kinase

Genetic deletion of Phosphoinositide 3-kinase (PI3Kγ) in mice (PI3Kγ -/- ) results in increased cAMP levels and enhanced ventricular contractility. We investigated whether the lack of PI3Kγ plays a role in cardiac contractility by altering intracellular calcium recycling. Isolated cardiomyocytes from PI3Kγ -/- mice showed significantly reduced calcium reuptake by sarcoendoplasmic reticulum (SR) following caffeine induced calcium release indicating that PI3Kγ locally regulates the function of SR. The intracellular calcium remained at elevated levels in the cardiomyocytes of PI3Kγ -/- for a prolonged period after caffeine treatment. This could be due to changes in phosphorylation of SERCA2, Ryanodine receptor (RyR 2 ) or phospholamban (PLN). In fact, when we looked at phosphorylation of PLN in cardiac lysates, a major regulator of cardiac contractility and relaxation, PI3Kγ -/- mice showed significantly reduced PLN phosphorylation compared to littermate controls. Previous studies from our laboratory suggested that absence of PI3Kγ leads to increase in protein phosphatase (PP) activity which could be possible reason for rapid dephosphorylation of PLN, resulting in inhibition of SERCA2 pump. We observed increased SR associated PP activity and PLN associated PP activity in PI3Kγ -/- mice. We also observed increased association of PP-1 and PP2A with PLN in the absence of PI3Kγ. The altered calcium handling in the cardiomyocytes of PI3Kγ -/- mice could be restored to the level of WT controls by okadaic acid mediated inhibition of PP, suggesting that PI3Kγ plays a role in regulating PP activity associated with SR. To test whether PI3Kγ activity is required for PLN dephosphorylation and SR calcium cycling, we used mice with cardiac specific overexpression of kinase dead PI3Kγ (PI3Kγ inact ) in global PI3Kγ -/- mice (PI3Kγ inact /PI3Kγ -/- ). PI3Kγ inact /PI3Kγ -/- mice showed restored PLN phosphorylation, improved caffeine induced calcium reuptake, decreased SR and PLN associated PP activity. These studies show a novel regulation of PP and SR calcium regulation by kinase independent function of PI3Kγ. The underlying mechanism of PP regulation by PI3Kγ will be presented.

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Cytosolic free Calcium and Intracellular Calcium Stores in Neutrophils from Hypertensive Subjects

Clinical Science ◽

10.1042/cs0690227 ◽

1985 ◽

Vol 69 (2) ◽

pp. 227-230 ◽

Cited By ~ 15

Author(s):

P. Daniel Lew ◽

Laurent Favre ◽

Francis A. Waldvogel ◽

Michel B. Vallotton

Keyword(s):

Essential Hypertension ◽

Intracellular Calcium ◽

Calcium Ionophore ◽

Calcium Handling ◽

Free Calcium ◽

Calcium Stores ◽

Cytosolic Free Calcium ◽

Intact Cells ◽

Intracellular Calcium Stores ◽

Calcium Indicator

1. Alterations in intracellular calcium have been implicated in the pathogenesis of essential hypertension. To see whether this is a generalized phenomenon we assessed cytosolic free calcium and intracellular calcium stores in neutrophils from normo- and hyper-tensive subjects, by trapping the fluorescent calcium indicator quin2 in intact cells. 2. Ten patients with untreated essential hypertension were compared with 10 age- and sex-matched normotensive subjects. The levels of cytosolic free calcium and intracellular calcium stores releasable by the calcium ionophore ionomycin did not differ. No significant relationship was found between blood pressure and the calcium parameters in all 20 subjects studied. 3. The results indicate that essential hypertension is not associated with a membrane defect in calcium handling of all human cell systems, leading to generalized increases in resting values of cytosolic free calcium. 4. Neutrophils do not appear to be a good model for intracellular calcium handling in vascular smooth muscle.

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Intracellular calcium handling heterogeneities in intact guinea pig hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00374.2003 ◽

2004 ◽

Vol 286 (2) ◽

pp. H648-H656 ◽

Cited By ~ 35

Author(s):

Rodolphe P. Katra ◽

Etienne Pruvot ◽

Kenneth R. Laurita

Keyword(s):

Guinea Pig ◽

Intracellular Calcium ◽

Calcium Release ◽

Optical Mapping ◽

Contractile Function ◽

Calcium Transient ◽

Calcium Transients ◽

Calcium Handling ◽

Excitation Light ◽

Intact Heart

Regional heterogeneities of ventricular repolarizing currents and their role in arrhythmogenesis have received much attention; however, relatively little is known regarding heterogeneities of intracellular calcium handling. Because repolarization properties and contractile function are heterogeneous from base to apex of the intact heart, we hypothesize that calcium handling is also heterogeneous from base to apex. To test this hypothesis, we developed a novel ratiometric optical mapping system capable of measuring calcium fluorescence of indo-1 at two separate wavelengths from 256 sites simultaneously. With the use of intact Langendorff-perfused guinea pig hearts, ratiometric calcium transients were recorded under normal conditions and during administration of known inotropic agents. Ratiometric calcium transients were insensitive to changes in excitation light intensity and fluorescence over time. Under control conditions, calcium transient amplitude near the apex was significantly larger (60%, P < 0.01) compared with the base. In contrast, calcium transient duration was significantly longer (7.5%, P < 0.03) near the base compared with the apex. During isoproterenol (0.05 μM) and verapamil (2.5 μM) administration, ratiometric calcium transients accurately reflected changes in contractile function, and, the direction of base-to-apex heterogeneities remained unchanged compared with control. Ratiometric optical mapping techniques can be used to accurately quantify heterogeneities of calcium handling in the intact heart. Significant heterogeneities of calcium release and sequestration exist from base to apex of the intact heart. These heterogeneities are consistent with base-to-apex heterogeneities of contraction observed in the intact heart and may play a role in arrhythmogenesis under abnormal conditions.

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Effects of Cocaine on Intracellular Calcium Handling In Cardiac and Vascular Smooth Muscle

PsycEXTRA Dataset ◽

10.1037/e496272006-013 ◽

1991 ◽

Author(s):

Cynthia L. Perreault ◽

◽

Kathleen G. Morgan ◽

James P. Morgan

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Intracellular Calcium ◽

Calcium Handling

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Regulation of intracellular calcium release during fertilization in sea urchin eggs

10.31274/rtd-180813-13280 ◽

1997 ◽

Author(s):

Shyh-Jye Lee

Keyword(s):

Intracellular Calcium ◽

Sea Urchin ◽

Calcium Release ◽

Sea Urchin Eggs ◽

Intracellular Calcium Release

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Faculty Opinions recommendation of Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1001269.37056 ◽

2002 ◽

Author(s):

Marcus Thelen

Keyword(s):

Intracellular Calcium ◽

Calcium Release ◽

Calcium Influx ◽

Extracellular Calcium ◽

Bacterial Clearance ◽

Cyclic Adp Ribose ◽

Intracellular Calcium Release

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Orientia tsutsugamushi Inhibits Apoptosis of Macrophages by Retarding Intracellular Calcium Release

Infection and Immunity ◽

10.1128/iai.70.8.4692-4696.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4692-4696 ◽

Cited By ~ 16

Author(s):

Mee-Kyung Kim ◽

Seung-Yong Seong ◽

Ju-Young Seoh ◽

Tae-Hee Han ◽

Hyeon-Je Song ◽

...

Keyword(s):

Intracellular Calcium ◽

Calcium Concentration ◽

Calcium Release ◽

Cytosolic Calcium ◽

Orientia Tsutsugamushi ◽

Cytosolic Calcium Concentration ◽

Infected Cells ◽

Intracellular Calcium Release ◽

Calcium Redistribution ◽

In Cells

ABSTRACT Orientia tsutsugamushi shows both pro- and antiapoptotic activities in infected vertebrate cells. Apoptosis of THP-1 cells induced by beauvericin was inhibited by O. tsutsugamushi infection. Beauvericin-induced calcium redistribution was significantly reduced and retarded in cells infected with O. tsutsugamushi. Antiapoptotic activities of O. tsutsugamushi in infected cells are most probably due to inhibition of the increase in the cytosolic calcium concentration.

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A SIMPLE MODEL FOR INTERACTION OF VOLTAGE AND CALCIUM DYNAMICS IN VIRTUAL VENTRICULAR TISSUE

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127403008776 ◽

2003 ◽

Vol 13 (12) ◽

pp. 3873-3886

Author(s):

O. V. ASLANIDI ◽

A. V. HOLDEN

Keyword(s):

Intracellular Calcium ◽

Calcium Release ◽

Cell Model ◽

Excitation Threshold ◽

Calcium Dynamics ◽

Variable Model ◽

Ventricular Cell ◽

Calcium Dependent ◽

Intracellular Ca ◽

A Site

A simple two-variable model is used to replace the formulation of calcium dynamics in the Luo–Rudy ventricular cell model. Virtual ventricular cell and tissue are developed and validated to reproduce restitution properties and calcium-dependent voltage patterns present in the original model. Basic interactions between the membrane potential and Ca 2+ dynamics in the virtual cell and a strand of the virtual tissue are studied. Intracellular calcium waves can be linked to both action potentials (APs) and delayed afterdepolarizations (DADs). An intracellular calcium wave propagating from the cell interior can induce an AP upon reaching the cell membrane. The voltage and the intracellular Ca 2+ patterns within the same cell can be highly desynchronized. In a one-dimensional strand of the virtual tissue calcium motion is driven by the AP propagation. However, calcium release can be induced upon certain conditions (e.g. Na + overload of the cells), which results in DADs propagating in the wake of AP. Such propagating DADs can reach the excitation threshold, generating a pair of extrasystolic APs. Collision of a propagating AP with a site of elevated intracellular Ca 2+ concentration does not affect the propagation under the normal conditions. Under Na + overload local elevation of the intracellular Ca 2+ leads to generation of an extrasystolic AP, which destroys the original propagating AP.

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