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

The most effective way to limit myocardial ischemic necrosis is reperfusion, but reperfusion itself may result in tissue injury, which has been difficult to separate from ischemic injury. This report identifies elements of apoptosis (programmed cell death) in myocytes as a response to reperfusion but not ischemia. The hallmark of apoptosis, nucleosomal ladders of DNA fragments (approximately 200 base pairs), was detected in ischemic/reperfused rabbit myocardial tissue but not in normal or ischemic-only rabbit hearts. Granulocytopenia did not prevent nucleosomal DNA cleavage. In situ nick end labeling demonstrated DNA fragmentation predominantly in myocytes. The pattern of nuclear chromatin condensation was distinctly different in reperfused than in persistently ischemic tissue by transmission electron microscopy. Apoptosis may be a specific feature of reperfusion injury in cardiac myocytes, leading to late cell death.

/pdf/reperfusion-injury-induces-apoptosis-in-rabbit-w99b92480o.pdf

Reperfusion injury induces apoptosis in rabbit cardiomyocytes.

ObjectivesIn view of the critical role of intracellular Ca2+-overload in the genesis of myocyte dysfunction and the ability of reactive oxygen species (ROS) to induce the intracellular Ca2+-overload, this article is concerned with analysis of the existing literature with respect to the role of oxida

Role of oxidative stress in cardiovascular diseases.

It has been commonly assumed that calcium, which normally serves important functions as a membrane stabilizer, metabolic regulator, and sec­ ond messenger, also can mediate anoxic and toxic cell death (Schanne et aI., 1979; Farber, 1981; Trump et aI., 1981). It is then postulated that when the plasma membrane becomes unduly permeable to calcium, the free cytosolic concentration (Ca2+) rises to toxic levels. As applied to the brain, this hypothesis predicts that loss of cellular calcium ho­ meostasis underlies selective neuronal vulnerability in ischemia, hypoglycemia, and epileptic seizures (Siesj6, 1981; Meldrum, 1983; Raichle, 1983; for further literature, see Siesj6 and Wieloch, 1985; Siesj6, 1988). It should be clearly understood that ischemia, particularly if dense, causes all cells to loose their calcium homeostasis. The hypothesis predicts, therefore, that some cells are more vulner­ able than others because they have a higher density of calcium channels in their plasma membranes. Presumably, this could lead to untolerable local in­ creases in calcium concentration. In a recent extension of the calcium hypothesis, it was speculated that increased calcium cycling across ischemia-damaged membranes leads to a sustained rise in Ca2 + j and slow calcium overload of mitochondria, thereby causing delayed neuronal death (Deshpande et aI., 1987; see also Martins et aI., 1988). Dux et aI. (1987), inducing transient isch­ emia in the gerbil, recently assessed the time course of mitochondrial calcium deposits in glia cells and in pyramidal cells of the hippocampus CAl sector and

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1989.20

Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis.

Because aerobic metabolic rates decrease in hypoxia-sensitive cells under oxygen-limiting conditions, the demand for glucose or glycogen for anaerobic glycolysis may rise drastically as a means of making up for the energetic shortfall. However, ion and electrical potentials typically cannot be sustained because of energy insufficiency and high membrane permeabilities; therefore metabolic and membrane functions in effect become decoupled. In hypoxia-tolerant animals, these problems are resolved through a number of biochemical and physiological mechanisms; of these metabolic arrest and stabilized membrane functions are the most effective strategies for extending tolerance to hypoxia. Metabolic arrest is achieved by means of a reversed or negative Pasteur effect (reduced or unchanging glycolytic flux at reduced O2 availability); and coupling of metabolic and membrane function is achievable, in spite of the lower energy turnover rates, by maintaining membranes of low permeability (probably via reduced densities of ion-specific channels). The possibility of combining metabolic arrest with channel arrest has been recognized as an intervention strategy. To date, the success of this strategy has been minimal, mainly because depression of metabolism through cold is the usual arrest mechanism used, and hypothermia in itself perturbs controlled cell function in most endotherms.

https://science.sciencemag.org/content/sci/231/4735/234.full.pdf

Defense strategies against hypoxia and hypothermia

Calcium entry in the calcium paradox

Calcium-mediated damage during post-ischaemic reperfusion.

Calcium exchange in cardiac muscle: a basic mechanism of drug action.

The effect of "sodium loading," of verapamil and of nifedipine on the gain in calcium and sodium, and on the loss of myoglobin, during the calcium paradox in adult rat hearts was examined. Raising cell sodium from 56.5 +/- 2.6 to 129.5 +/- 10.2 mumol sodium/gram dry weight did not alter the degree or rate of calcium gain or myoglobin release during calcium repletion after long periods (greater than 2 minutes) of calcium-free perfusion; under these conditions, and in the presence of 10 micrograms/liter verapamil, calcium gain was enhanced. However, after shorter periods (0.5-1.5 minutes), of calcium-free perfusion, calcium gain was enhanced in "sodium-loaded" hearts, even in the absence of verapamil, and particularly during the early stages of repletion. The presence of 1 and 10 mumol/liter dl-verapamil and 1 mumol/liter nifedipine before, during, and after 10 minutes of calcium-free perfusion significantly (P less than 0.01) slowed the early (up to 1 minute for verapamil and 2 minutes for nifedipine) but not the late gain in calcium. When verapamil was present, the late gain in calcium was actually enhanced. These agents also abolished the early (45 seconds) but not the late (greater than 2 minutes) gain in sodium that occurs during repletion. We propose that the gain in calcium that occurs during calcium repletion after a period of calcium-free perfusion can be divided into at least two phases (early and late), and that the early phase contains a verapamil/nifedipine-sensitive component and a verapamil/nifedipine-insensitive component, the latter probably involving sodium-calcium exchange.

Winifred G. Nayler

Papers

Calcium entry in the calcium paradox

Calcium-mediated damage during post-ischaemic reperfusion.

Calcium exchange in cardiac muscle: a basic mechanism of drug action.

Calcium, sodium, and the calcium paradox.

Calcium antagonists: a new class of drugs.