Author
David A. Eisner
Other affiliations: University of Oxford, Research Triangle Park, University of Cambridge ...read more
Bio: David A. Eisner is an academic researcher from University of Manchester. The author has contributed to research in topics: Ryanodine receptor & Cardiac muscle. The author has an hindex of 69, co-authored 256 publications receiving 13473 citations. Previous affiliations of David A. Eisner include University of Oxford & Research Triangle Park.
Topics: Ryanodine receptor, Cardiac muscle, Calcium, Intracellular pH, SERCA
Papers published on a yearly basis
Papers
More filters
••
TL;DR: The factors that regulate and fine-tune the initiation and termination of release of Ca, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i are reviewed.
Abstract: Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca 2+ ] i ). Normal function requires that [Ca 2+ ] i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca 2+ ] i .
465 citations
••
TL;DR: Voltage clamp experiments on isolated sheep Purkinje fibres showed an increase of the steady state outward membrane current, over the potential range −65 mV to −15 mV, in the presence of tetrodotoxin, considered to be the steadystate component of the fast sodium current (INa), resulting from the crossover of the activation and inactivation curves which govern the opening of the sodium channel.
Abstract: Voltage clamp experiments on isolated sheep Purkinje fibres showed an increase of the steady state outward membrane current, over the potential range -65mV to -15 mV, in the presence of tetrodotoxin (TTX, 3.10(-5 M). This "window" current is considered to be the steady state component of the fast sodium current (INa), resulting from the crossover of the activation and inactivation curves which govern the opening of the sodium channel. TTX had no significant effect on the reversal potential, activation curve, kinetics or instantaneous I-V relationship of the pacemaker current IK2. The window found in these experiments extends to potentials well into the range of the action potential plateau. Consequently small changes of the steady state INa might have large effects on the action potential duration. The effects of TTX and local anaesthetics are discussed in this context.
413 citations
••
TL;DR: This review illustrates how analysis of the control of calcium requires an integrated approach in which several systems are considered and predicts that, under some conditions, the above interactions can result in instability rather than ordered control of contractility.
Abstract: The control of intracellular calcium is central to regulation of contractile force in cardiac muscle. This review illustrates how analysis of the control of calcium requires an integrated approach in which several systems are considered. Thus, the calcium content of the sarcoplasmic reticulum (SR) is a major determinant of the amount of Ca(2+) released from the SR and the amplitude of the Ca(2+) transient. The amplitude of the transient, in turn, controls Ca(2+) fluxes across the sarcolemma and thence SR content. This control of SR content influences the response to maneuvers that modify, for example, the properties of the SR Ca(2+) release channel or ryanodine receptor. Specifically, modulation of the open probability of the ryanodine receptor produces only transient effects on the Ca(2+) transient as a result of changes of SR content. These interactions between various Ca(2+) fluxes are modified by the Ca(2+) buffering properties of the cell. Finally, we predict that, under some conditions, the above interactions can result in instability (such as alternans) rather than ordered control of contractility.
309 citations
••
TL;DR: Investigation of beat-to-beat alternation in the amplitude of the systolic Ca2+ transient (Ca2+ alternans) found that it was found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitudes of the Ca2- transient, which results from the steep dependence on SR Ca2+.
Abstract: The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca 2+ transient (Ca 2+ alternans) is due to changes of sarcoplasmic reticulum (SR) Ca 2+ content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca 2+ content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca 2+ transient. Confocal measurements showed that the larger transients resulted from propagation of Ca 2+ waves. SR Ca 2+ content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca 2+ transient amplitude. After a large transient, if SR Ca 2+ content was elevated by brief exposure of the cell to a Na + -free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca 2+ content are sufficient to produce alternans. The dependence of Ca 2+ transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca 2+ efflux from the cell was also a steeper function of SR Ca 2+ content than under control. We attribute these steeper relationships to the fact that the larger responses in alternans depend on wave propagation and that wave propagation is a steep function of SR Ca 2+ content. In conclusion, alternans of systolic Ca 2+ appears to depend on alternation of SR Ca 2+ content. This, in turn results from the steep dependence on SR Ca 2+ content of Ca 2+ release and therefore Ca 2+ efflux from the cell as a consequence of wave propagation.
307 citations
••
TL;DR: In this article, the authors show that sarcoplasmic reticulum (SR) Ca2+ content reflects the balance between Ca2 uptake (via SERCA) and Ca2 efflux via ryanodine receptor (RyR).
Abstract: Heart failure (HF) is a leading cause of death and enormous effort has focused at understanding the molecular and cellular mechanisms of the decreased cardiac contractility. While changes of other components contribute, it is generally agreed that much of the contractile deficit is due to reduced myocyte Ca2+ transients.1,2 Alterations in Ca2+ current ( I Ca) and action potential characteristics are also seen in HF, but a central factor limiting Ca2+ transient amplitude is a decrease of sarcoplasmic reticulum (SR) Ca2+ content.3–6 HF is extremely complex, but it is easy to appreciate how reduced SR Ca2+ content would reduce SR Ca2+ release, myofilament activation, and contractility. Despite agreement that SR Ca2+ content is reduced in HF, controversy exists about why SR content is low.
SR Ca2+ content reflects the balance between Ca2+ uptake (via SERCA) and Ca2+ efflux via ryanodine receptor (RyR). Thus, reduced SR content in HF must be due to reduced Ca2+ pumping by SERCA or increased SR Ca2+ leak via RyRs. Both are supported by experimental data (below). Transsarcolemmal Ca2+ fluxes also affect SR Ca2+ load. That is, reduced Ca2+ influx (eg, via I Ca) or enhanced Ca2+ extrusion via Na+-Ca2+ exchange (NCX) can unload the SR. Results are not unanimous, but most groups find little alteration in peak I Ca density in HF, while many find evidence of enhanced NCX expression and function.1,2 Increased NCX function can compete with SERCA during [Ca2+]i decline, extruding more Ca2+ from the cell and depleting the SR. In the new steady state, a larger fraction of activating Ca2+ also enters the cell at each beat in HF (eg, smaller Ca2+ release causes less …
275 citations
Cited by
More filters
••
TL;DR: Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important and spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
Abstract: Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important. It is crucial to the very process that enables the chambers of the heart to contract and relax, a process called excitation-contraction coupling. It is important to understand in quantitative detail exactly how calcium is moved around the various organelles of the myocyte in order to bring about excitation-contraction coupling if we are to understand the basic physiology of heart function. Furthermore, spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
4,216 citations
••
TL;DR: Current studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains, and microglial cells are considered the most susceptible sensors of brain pathology.
Abstract: Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.
2,998 citations
••
TL;DR: The calcium spark is the consequence of elementary events underlying excitation-contraction coupling and provides an explanation for both spontaneous and triggered changes in the intracellular calcium concentration in the mammalian heart.
Abstract: Spontaneous local increases in the concentration of intracellular calcium, called "calcium sparks," were detected in quiescent rat heart cells with a laser scanning confocal microscope and the fluorescent calcium indicator fluo-3 Estimates of calcium flux associated with the sparks suggest that calcium sparks result from spontaneous openings of single sarcoplasmic reticulum (SR) calcium-release channels, a finding supported by ryanodine-dependent changes of spark kinetics At resting intracellular calcium concentrations, these SR calcium-release channels had a low rate of opening (approximately 00001 per second) An increase in the calcium content of the SR, however, was associated with a fourfold increase in opening rate and resulted in some sparks triggering propagating waves of increased intracellular calcium concentration The calcium spark is the consequence of elementary events underlying excitation-contraction coupling and provides an explanation for both spontaneous and triggered changes in the intracellular calcium concentration in the mammalian heart
1,913 citations
••
TL;DR: In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial.
Abstract: The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.
1,715 citations
••
TL;DR: Genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene, and single strand conformation polymorphism and DNA sequence analyses suggest that mutations in SCN 5A cause chromosome 3-linked LQt and indicate a likely cellular mechanism for this disorder.
1,550 citations