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 relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.

/pdf/diabetogenic-action-of-streptozotocin-relationship-of-dose-2a2gw8ducg.pdf

Diabetogenic action of streptozotocin: relationship of dose to metabolic response.

Multiple small injections of streptozotocin in mice produce pancreatic insulitis, with progression to nearly complete beta cell destruction and diabetes mellitus. The timing and appearance of the inflammatory islet lesions suggest but do not prove that streptozotocin acts by initiating a cell-mediated immune reaction. Ultrastructural evidence of abundant type C viruses within beta cells of treated mice suggests that streptozotocin may activate murine leukemia virus in vivo in susceptible hosts.

http://science.sciencemag.org/content/sci/193/4251/415.full.pdf

Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus.

Streptozotocin (STZ) is an antibiotic that produces pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this unit are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition.

/pdf/streptozotocin-induced-diabetic-models-in-mice-and-rats-3uvh857gzb.pdf

Streptozotocin‐Induced Diabetic Models in Mice and Rats

III. Calcium Fluxes in Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . 41 A. Invertebrate Nervous Tissue . . . . . . . . . . . . . . . . . . . . . . . . 41 1. The Squid Axon . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 a) Calcium Efflux . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 b) Calcium Influx . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 c) External Calcinm-Dependent Sodium Efflux . . . . . . . . . . . . . . 48 d) Do Cardiac Glycosides Directly Affect the Calcium Fluxes ? . . . . . . . 49 e) A Model for the Na-Ca Exchange Mechanism in Squid Axons . . . . . . 50 2. Nerves of Other Invertebrates . . . . . . . . . . . . . . . . . . . . . . 53

The interrelationship between sodium and calcium fluxes across cell membranes

SummaryStreptozotocin is a highly effective cytotoxic agent for pancreatic B-cells. After intravenous administration of 65 mg streptozotocin per kg, damage to B-cells is apparent as early as one hour after intravenous administration of the drug. Frank necrosis associated with phagocytosis is best seen after 7 hours, when pancreatic insulin release and hypoglycemia are also noted. By 24 hours, pancreatic insulin content is reduced to 5% of normal or less. While the B-cytotoxic effects of streptozotocin resemble those of alloxan, their specificity is very much greater, as demonstrated by the wide margin between diabetogenic dose and general toxicity.

Studies of the diabetogenic action of streptozotocin.

Pancreatic cells from neonatal rats, isolated by repeated exposure to a mixture of trypsin and collagenase, were cultured in monolayer for periods up to 19.5 days. This preparation was characterized by: (1) light microscopy combined with morphometric analysis; and (2) measurements of immunoreactive insulin (IRI) and protein content of cultured cells and of the amounts of IRI released into the culture medium. The major problem encountered was the rapid proliferation of fibroblastoid cells which tended to overgrow the culture. The decantation of the primary cell suspension after 14 hrs of culture produced a preparation enriched in epithelioid cells, which appeared as clusters. Contained in these clusters were aldehyde-thionin positive cells, presumably B cells. The number of clusters of epithelioid cells did not change over an 8.5 day culture period, but the size of the individual clusters diminished with time. The protein content of cultured cells, which probably reflects the degree of contamination by fib...

Monolayer Cell Culture of Neonatal Rat Pancreas: Light Microscopy and Evidence for Immunoreactive Insulin Synthesis and Release

Enhancement by caffeine of glucagon-induced and tolbutamide-induced insulin release from isolated fœtal pancreatic tissue

Organ culture of fetal rat pancreas. II. Insulin release induced by amino and organic acids, by hormonal peptides, by cationic alterations of the medium and by other agents.

A.E. Lambert

Papers

Studies of the diabetogenic action of streptozotocin.

Monolayer Cell Culture of Neonatal Rat Pancreas: Light Microscopy and Evidence for Immunoreactive Insulin Synthesis and Release

Enhancement by caffeine of glucagon-induced and tolbutamide-induced insulin release from isolated fœtal pancreatic tissue

Organ culture of fetal rat pancreas. II. Insulin release induced by amino and organic acids, by hormonal peptides, by cationic alterations of the medium and by other agents.

Organ culture of fetal rat pancreas. I. Insulin release induced by caffeine and by sugars and some derivatives.