Calcium Sparks: Elementary Events Underlying Excitation-Contraction Coupling in Heart Muscle

Cheng, Heping; Lederer, W. Jonathan; Cannell, Mark B.

doi:10.1126/science.8235594

Cited by 1,823 publications

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“…Local Ca 2+ i transients ('Ca 2+ sparks') are found in both cardiac and skeletal muscle [32][33][34] , as well as in neurites of PC12 cells and of hippocampal neurons in culture 35 . We searched for similar transients in our preparation.…”

Section: Spontaneous Ca 2+ I Transients In Presynaptic Terminalsmentioning

confidence: 99%

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

et al. 2000

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articlesThe building block of synaptic transmission is the quantum, the minimal increment of postsynaptic signals 1 . At vertebrate neuromuscular junctions, the quantum may be equated with spontaneous signals obtained in the absence of presynaptic action potentials, called miniature currents (or potentials) and believed to be due to release of one neurotransmitter vesicle. For central synapses, this issue remains an open question, as large miniature currents are suggested to arise from the concerted release of several presynaptic vesicles and to be the sum of several quanta 2-5 . Such multivesicular miniature events could reflect tetrodotoxinresistant action potentials in presynaptic terminals 6 . Another explanation comes from evidence for functional intracellular Ca 2+ stores in presynaptic terminals. First, inositoltrisphosphate (InsP 3 ) receptors are immunolocalized in presynaptic terminals of the deep cerebellar nuclei and retina 7,8 . Second, at the frog neuromuscular junction, agents that affect ryanodine-sensitive Ca 2+ stores also regulate presynaptic intracellular Ca 2+ (Ca 2+ i ) rises and acetylcholine release during high-frequency stimulation 9,10 . Third, action-potential-evoked release of acetylcholine at synapses in Aplysia buccal ganglia is inhibited by ryanodine and augmented by presynaptic injection of cyclic ADP ribose 11 . Fourth, caffeine and/or ryanodine modify presynaptic Ca 2+ i signals in autonomic ganglia 12,13 and in photoreceptors 14 . Finally, in hippocampal pyramidal cells, caffeine or thapsigargin can increase the frequency of miniature IPSCs 15 . Hence, spontaneous Ca 2+ release from presynaptic Ca 2+ stores may provide the synchronization mechanism that leads to multivesicular miniatures. However, except for one study that gave negative results in cultured retinal amacrine cells 16 , this possibility has not been tested systematically.To assess the contribution of intracellular Ca 2+ stores to neurotransmitter release, we monitored the amplitude distribution of miniature synaptic currents while manipulating potential presynaptic Ca 2+ stores. Using cerebellar interneuron-Purkinje cell synapses, in which large miniature synaptic currents are prominent, we found that the largest mIPSCs result from multivesicular release and depend on Ca 2+ mobilization from ryanodine-sensitive presynaptic stores. Further, two-photon confocal microscopy showed ryanodine-sensitive intracellular Ca 2+ i transients highly localized to presumed release sites, which may underlie large miniature currents. RESULTSMiniature IPSCs recorded in cerebellar Purkinje cells, at -60 mV under symmetrical Cl -concentrations and in the presence of tetrodotoxin (TTX) and ionotropic glutamate receptor blockers, showed mean amplitudes of 125 ± 9 pA (n = 28 cells), larger than for most neurons (Fig. 1a). Amplitude histograms had a distinct peak for values less than 200 pA, followed by a long tail with amplitudes up to 1500 pA (Fig. 1b). Spurious summation of independent events did not contribute to the generation of lar...

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Section: Spontaneous Ca 2+ I Transients In Presynaptic Terminalsmentioning

confidence: 99%

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

et al. 2000

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“…Discrete, non-propagating elementary Ca 2+ release events have been characterized in a variety of excitable and non-excitable cell types (for reviews see [73,74]), for both RyRs ('Ca 2+ sparks'; [75][76][77][78]) and IP 3 Rs [70,79,80]. Ca 2+ sparks represent Ca 2+ release from a restricted number of clustered RyRs opening in concert [81].…”

Section: Elementary Ip 3 -Induced Ca 2+ Release Events In Cardiac Myomentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

169

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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“…Experimentally, single Ca 2+ release events can be observed by confocal microscopy as "Ca 2+ sparks" that occur spontaneously in quiescent cardiac myocytes [42]. These Ca 2+ sparks arise from the concerted activation of a whole cluster of RyRs [43,177,181].…”

Section: Excitation-contraction Couplingmentioning

confidence: 99%

“…This high junctional [Ca 2+ ] decays rapidly by diffusion into the submembrane space and then further into the bulk cytosol, where it peaks later and at much lower concentrations than in the cleft (at ∼1.5 µM in the submembrane space and ∼0.5 µM in the bulk cytosol [174,209]). Due to the spatial and temporal heterogeneity of [Ca 2+ ] throughout different compartments of the cytosol, the term of "Ca 2+ microdomains" was coined [160], with the junctional cleft being the best characterized Ca 2+ microdomain in cardiac myocytes.Experimentally, single Ca 2+ release events can be observed by confocal microscopy as "Ca 2+ sparks" that occur spontaneously in quiescent cardiac myocytes [42]. These Ca 2+ sparks arise from the concerted activation of a whole cluster of RyRs [43,177,181].…”

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Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

218

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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Calcium Sparks: Elementary Events Underlying Excitation-Contraction Coupling in Heart Muscle

Cited by 1,823 publications

References 43 publications

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Excitation-contraction coupling and mitochondrial energetics

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