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.

Cardiac excitation–contraction coupling

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.

Physiology of Microglia

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

https://science.sciencemag.org/content/sci/262/5134/740.full.pdf

Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle

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.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.3.763

Sodium/Calcium Exchange: Its Physiological Implications

https://www.cell.com/cell/pdf/0092-8674(95)90359-3.pdf

SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome

Over the last 2 decades, understanding of the mechanisms that underlie heart failure (HF) has grown enormously. One of the key concepts is that HF is associated with profound alterations in myocardial calcium handling and excitation-contraction coupling.

Article see p 970

Most of the calcium that activates contraction comes from the sarcoplasmic reticulum (SR). It leaves the SR through a specialized release channel known as the ryanodine receptor (RyR). The probability that an RyR is open and can therefore allow Ca to leave the SR into the cytoplasm is increased by an increase in the concentration of either cytosolic or SR (luminal) Ca concentration. During the normal heartbeat, sarcolemmal Ca channels open and some of the entering Ca binds to the RyRs, making them open, thereby triggering the release of a much greater amount of Ca from the SR into the cytosol. This Ca release causes a rapid rise of cytosolic Ca to levels that activate the myofilaments and initiate contraction. After termination of release of Ca from the SR (because of closure of RyRs), cytosolic Ca levels decline rapidly and relaxation occurs. Ca is rapidly removed from the cytosol by 2 major systems: the sarcoendoplasmic reticulum Ca ATPase and the sarcolemmal sodium/calcium exchanger. Sarcoendoplasmic reticulum Ca ATPase pumps Ca back into the SR, whereas sarcolemmal sodium/calcium exchanger pumps 1 Ca2+ out in exchange for the influx of 3 Na+ ions into the cell. This rapid cycle of Ca release and reuptake is known as the systolic Ca transient, and it is one of the main factors that control force of contraction in the heart. It is worth emphasizing that the normal Ca transient depends on the RyRs being virtually closed in diastole, opening very briefly to produce the systolic increase of Ca, and then closing to allow …

A Tale of Two Leaks

A study of intracellular calcium oscillations in sheep cardiac Purkinje fires

An important advance in our understanding of excitation-contraction coupling was provided by the demonstration of calcium sparks attributed to the release of calcium ions from single sarcoplasmic reticulum (SR) release sites (Cheng, Lederer & Cannell, 1993). Subsequent work has shown that these sparks summate to produce the normal systolic Ca2P transient in cardiac muscle (L6pez-Lopez, Shacklock, Balke & Wier, 1994). Sparks have also been found in both skeletal and smooth muscle (Nelson et al. 1995; Klein, Cheng, Santana, Jiang, Lederer & Schneider, 1996). In cardiac and skeletal muscle the sparks activate contraction whereas in smooth muscle they appear preferentially to activate Ca2+-activated K+ currents and thereby promote relaxation (Nelson et al. 1995). In smooth muscle the sparks may be the explanation for the spontaneous transient outward currents previously observed (Benham & Bolton, 1986). The sparks do not appear to be restricted to muscle, or indeed to systems using the ryanodine receptor channel (RyR), as closely related phenomena (puffs) have been found in other cells such as the Xei7 opus oocyte where Ca2+ release occurs through the InsP3 receptor channel (Yao, Choi & Parker, 1995). These puffs may underlie the spontaneous outward currents seen in 2ultured neurones (Satin & Adams, 1987).

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1996.sp021744

A sideways look at sparks, quarks, puffs and blips.

Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+‐Ca2+ exchange (NCX) current, leading to delayed after‐depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage‐clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine‐induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L‐type Ca2+ current, ICa‐L, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi‐channels, TRPC1/4/5, L‐type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1113/JP282168

David A. Eisner

Papers

A Tale of Two Leaks

A study of intracellular calcium oscillations in sheep cardiac Purkinje fires

A sideways look at sparks, quarks, puffs and blips.

Interaction of background Ca2+ influx, sarcoplasmic reticulum threshold and heart failure in determining propensity for Ca2+ waves in sheep heart

Enhanced calcium release at specialised surface sites compensates for reduced t-tubule density in neonatal sheep atrial myocytes.