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

How does endothelin-1 cause a sustained increase in intracellular sodium and calcium which lead to hypertrophy?

A cellular basis for lidocaine's anti-arrhythmic action [proceedings].

Citation analysis is now big business, to the point of supporting ‘impact factor mania’ (Casadevall & Fang, 2014). As a consequence of this exaggerated importance being placed on citations as discussed in detail below, many reputable scientific organisations have endorsed the San Francisco declaration (DORA) (2012) to improve the ways in which the output of scientific research is evaluated. Originally Garfield and Sher simply wanted to select the most significant journals to list in Current

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP277847

Misleading with citation statistics

8 – The Regulation of Tension in Heart Muscle by Intracellular Sodium

In this paper we review the effects of cardiac glycosides on the electrophysiological properties of mammalian cardiac muscle. Cardiac glycosides produce an initial prolongation of the action potential due to inhibition of the electrogenic Na-K pump current. This is then followed by a gradual decrease of action potential duration to less than control length. The origin of this decrease is uncertain. Cardiac glycosides also produce a transient depolarization which follows the action potential and which can produce a spontaneous action potential. This transient depolarization is produced by a transient inward current which results from a Ca-activated conductance. The triggering increase of [Ca2+]i originates from the spontaneous release of Ca ions from the sarcoplasmic reticulum (s. r.). Both this spontaneous release and the resulting transient inward current can be abolished by inhibitors of s. r. function such as caffeine and ryanodine. As well as these oscillations of [Ca2+]i which follow repolarization, there are also spontaneous oscillations in the absence of stimulation. These spontaneous oscillations, which also result from release of Ca from the sarcoplasmic reticulum, interfere with the systolic rise of Ca produced by stimulation. Thus the Ca oscillations are not only responsible for the cardiac arrhythmias produced by digitalis but also compromise the magnitude of the positive inotropic effect.

David A. Eisner

Papers

How does endothelin-1 cause a sustained increase in intracellular sodium and calcium which lead to hypertrophy?

A cellular basis for lidocaine's anti-arrhythmic action [proceedings].

Misleading with citation statistics

8 – The Regulation of Tension in Heart Muscle by Intracellular Sodium

Electrophysiological effects of cardiac glycosides