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

Familial Mediterranean fever. A survey of 470 cases and review of the literature

Publisher Summary This chapter discusses the formal genetics of mouse anemias and their significance for an analysis of patterns of mammalian gene action. It also describes normal hemopoietic development, homeostasis, and hemoglobin polymorphism. Anemias are classified into five categories—(1) anemias of maturation arrest, (2) anemias involving defects in iron utilization, (3) anemias involving greatly reduced erythrocyte life-span, (4) hemoglobinopathies, and (5) anemias almost secondary to genetically induced defects. During the total life of a mouse, including prenatal development, hemopoiesis takes place in four different sites. Although hemopoiesis continues in the liver until birth and for a brief time thereafter, hemopoiesis (largely myelopoiesis) commences in the spleen on fetal day 15 or 16 and in the marrow around the time of birth. Hematologically normal adult mice from many different inbred strains regularly produce more than one kind of hemoglobin. There is a widespread genetic polymorphism at both the Hba locus, determining the α-globin structure and the Hbb locus, determining the β-globin structure, and both the loci involve considerable genetic complexity.

Hereditary Anemias of the Mouse: A Review for Geneticists*

Familial Mediterranean fever: risk factors, causes of death, and prognosis in the colchicine era.

1. The yield of mitochondria isolated from perfused hearts subjected to 30 min ischaemia followed by 15 min reperfusion was significantly less than that for control hearts, and this was associated with a decrease in the rates of ADP-stimulated respiration. 2. The presence of 0.2 microM cyclosporin A (CsA) in the perfusion medium during ischaemia and reperfusion caused mitochondrial recovery to return to control values, but did not reverse the inhibition of respiration. 3. A technique has been devised to investigate whether the Ca(2+)-induced non-specific pore of the mitochondrial inner membrane opens during ischaemia and/or reperfusion of the isolated rat heart. The protocol involved loading the heart with 2-deoxy[3H]glucose ([3H]DOG), which will only enter mitochondria when the pore opens. Subsequent isolation of mitochondria demonstrated that [3H]DOG did not enter mitochondria during global isothermic ischaemia, but did enter during the reperfusion period. 4. The amount of [3H]DOG that entered mitochondria increased with the time of ischaemia, and reached a maximal value after 30-40 min of ischaemia. 5. CsA at 0.2 microM did not prevent [3H]DOG becoming associated with the mitochondria, but rather increased it; this was despite CsA having a protective effect on heart function similar to that shown previously [Griffiths and Halestrap (1993) J. Mol. Cell. Cardiol. 25, 1461-1469]. 6. The non-immunosuppressive CsA analogue [MeAla6]cyclosporin was shown to have a similar Ki to CsA on purified mitochondrial peptidyl-prolyl cis-trans-isomerase and mitochondrial pore opening, and also to have a similar protective effect against reperfusion injury. 7. Using isolated heart mitochondria, it was demonstrated that pore opening could become CsA-insensitive under conditions of adenine nucleotide depletion and high matrix [Ca2+] such as may occur during the initial phase of reperfusion. The apparent increase in mitochondrial [3H]DOG in the CsA-perfused hearts is explained by the ability of the drug to stabilize pore closure and so decrease the loss of [3H]DOG from the mitochondria during their preparation.

Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion.

The Effect of Local Roentgen Irradiation on the Biological Behavior of a Transplantable Mouse Carcinoma. I. Increased Frequency of Pulmonary Metastasis

Oncogene expression in human leukemia

Hyperplastic and Early Neoplastic Changes in the Ovaries of Mice After Genic Deletion of Germ Cells

Fluorine 19 nuclear magnetic resonance (NMR) studies of intracellular fluorinated calcium chelators provide a useful strategy for the determination of cytosolic free calcium levels in cells and perfused organs. However, the fluorinated chelator with the highest affinity for calcium ions which has been described to date. 1,2-bis-(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5FBAPTA), exhibits a dissociation constant (K/sub d/) value 5- to 10-fold greater than the intracellular calcium concentration levels in most cell types, thus limiting the ability of fluorine NMR to report these concentrations reliably. The authors have consequently designed and synthesized several fluorinated calcium chelators with higher affinity for calcium. The best of these, 2-(2-amino-4-methyl-5-fluorophenoxy)-methyl-8 aminoquinidine-N,N,N',N'-tetraacetic acid (quinMF), has a K/sub d/ value approx. 10 times lower than that of 5FBAPTA. Several of the newly synthesized indicators have different chemical shifts for the calcium complexed and uncomplexed chelators to allow the simultaneously use of two indicators. In addition to providing information about the level of cytosolic free calcium, chelators containing a quinoline ring exhibit considerable sensitivity to magnesium levels and hence have potential application for the determination of cytosolic-magnesium concentrations. Application of these chelators is illustrated by determination of the cytosolic-free calcium level in erythrocytes. Use of quinMF, the chelator with themore » lowest K/sub d/ value, gives a calcium value of 25-30 nM.« less

Synthesis and characterization of 19F NMR chelators for measurement of cytosolic free Ca.

Interrelationships between a chemical carcinogen and hormonal status in cervical carcinogenesis were investigated. No significant effects of castration or added estrogen stimulation were detected under conditions of prolonged exposure to methylcholanthrene by cervical painting or continuous exposure of the endocervical epithelium to a methylcholanthrene-coated thread. When the time of exposure to methylcholanthrene-coated threads was reduced to 4 weeks a low incidence of cervical carcinoma appeared in castrates providing a baseline for determination of the effect of subsequent systemic treatment with estrogenic hormone. The incidence of cervical carcinoma was increased and the average laten period decreased in strains A/Sn C3HeB/FeJ and 129/J when systemic treatment with diethylstilbestrol (DES) followed a 4-week exposure of the castrate endocervical epithelium to a methylcholanthrene-coated thread. The incidence of carcinoma increased from 13.2-90.2% when 33% DES-cholesterol pellets were administered. The average latent period was reduced from 12.3-6.7 months. 10% DES-cholesterol pellets increased the incidence of carcinoma from from 3.3-19.1% with lesser shortening of the average latent period. Plain-thread stimulation of the castrate endocervical epithelium for 4 weeks followed by 33% DES pellets produced an incidence of 7.1% carcinoma in the 3 strains. 10% DES pellets produced carcinoma in 1.5% of strain A castrates. Plain-thread stimulation for 4 weeks produced no carcinomas among 78 mice. The promoting action of estrogen in these experiments is discussed. (authors)

Carcinogenesis of the uterine cervix in mice: effect of diethylstilbestrol after limited application of 3-methylcholanthrene.

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