Enhanced uptake of calcium by transforming lymphocytes

Whitney, Richard B.; Sutherland, Robert M.

doi:10.1016/0008-8749(72)90091-3

Cited by 152 publications

(22 citation statements)

References 18 publications

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“…It has been shown, for example, that intracellular levels of both calcium ions (21,22) and cyclic GMP (23,24) increase after mitogen binding. In addition, A-23187, which mediates calcium ion transport, and TPA, which elevates cyclic GMP levels (4), are independently mitogenic for lymphocytes (5-7).…”

Section: Discussionmentioning

confidence: 99%

Modulation of lymphocyte mitogenesis.

Wang¹,

McClain²,

Edelman³

1975

Proc. Natl. Acad. Sci. U.S.A.

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Comparisons of the stimulation of normal lymphocytes and lymphoma cells by tetrameric concanavalin A (Con A) and dimeric succinyl-Con A suggest that both stimulatory and inhibitory signals operate to modulate mitogenesis. Synergistic effects can be obtained for the stimulatory event using lectins, phorbol esters, and calcium ionophores, all of which are independently mitogenic for lymphocytes. The inhibitory effects of high doses of Con A could be mimicked by the simultaneous addition of the phorbol ester and Con A under conditions in which both reagents are optimally mitogenic when used alone. No inhibition of stimulation was found, however, when succinyl-Con A was used with phorbol ester under the same conditions. Moreover, when lymphocytes were cultured with Con A in the presence of succinyl-Con A, the inhibitory effect of the native lectin was seen at lower doses than in the absence of the derivative. These observations suggest that the stimulatory and inhibitory portions of the dose-response curve can be manipulated independently and may be mediated by two distinct signals. It is likely the signal for the inhibition of cell proliferation is regnlated by the same cell surface modulating assembly that controls the mobility of cell surface receptors.Since Nowell's discovery that phytohemagglutinin (PHA), the lectin from Phaseolus vulgarms, can induce blast transformation in normal leukocytes (1), the mitogenic stimulation of lymphocytes has been studied extensively as a model for both antigenic activation and growth control. Mitogens show characteristic unimodal dose--response curves for a given population of lymphocytes, i.e., concentrations significantly below or above the optimum show no stimulation. A typical example of this behavior is seen in the stimulation of lymphocytes by the lectin concanavalin A (Con A), whose structure (2) and binding specificity (3) have been extensively characterized.Much effort has been directed at understanding the stimulation induced by low doses of lectins and other agents. Although their causal connections remain to be established, it has been shown that calcium ionophores and agents capable of stimulating synthesis of guanosine 3': 5'-cyclic inonophosphate (cyclic GMP) (4), such as phorbol esters, are also mitogenic (5-7). Much less attention has been directed, however, at the inhibitory effects of high doses of lectins and these agents.In this paper, we describe several approaches to the analysis of the stimulatory and inhibitory effects responsible for the characteristic mitogenic dose-response curve. We have found that divalent succinvl-Con A shows stimulatory but not Abbreviations: PHA, phytohemagglutinin; Con A, concanavalin A; TPA, 12-0-tetradecanoyl-phorbol-13-0-acetate; cyclic GMP, guanosine 3' :5'-cyclic monophosphate; CSMA, cell surface modulating assembly. 1917inhibitory properties. Moreover, lectins, calcium ionophores, and phorbol esters are synergistic in stimulating mitogenesis. Addition of phorbol ester to higher doses of Con A, however, results in ...

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Section: Discussionmentioning

confidence: 99%

Modulation of lymphocyte mitogenesis.

Wang¹,

McClain²,

Edelman³

1975

Proc. Natl. Acad. Sci. U.S.A.

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“…It is possible that Ca++ is involved in the effect of most, if not all, agents known to increase cyclic GMP levels, since most of these agents are thought to elevate cytoplasmic Ca++. These compounds include, in addition to the agents already discussed, a-adrenergic agents (15,16), NaF (17,18), and phytohemagglutinin (18,19 The observation that cyclic GMP levels are elevated under conditions that are accompanied by a contraction of smoothmuscular tissues and increased secretion of salivary glands may suggest a regulatory role of cyclic GMP in these processes. However, such an assumption would be premature considering other findings.…”

Section: Effects Of Acetylcholine On Cyclic Nucleotides In Ductusmentioning

confidence: 99%

The Importance of Calcium Ions for the Regulation of Guanosine 3′:5′-Cyclic Monophosphate Levels

Schultz

Hardman

Schultz

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

247

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Guanosine 3': 5'-cyclic monosphosphate (cyclic GMP) levels in the ductus deferens of the rat were increased 2-to 3-fold by acetylcholine (10-1000 MM) or by 125 mM KCI, while adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were not changed. After incubation for 30 min in the absence of Ca++, cyclic GMP control levels were decreased by 85% and were not affected by acetylcholine or KCI. The readdition of Ca++ (1.8 mM) for 3 min to Ca++-deprived tissue partially restored basal cyclic GMP levels and the effects of acetylcholine and KCI. The addition of Sr++ (3.6 mM) or of Ba++ (1.8 or 10 mM) also caused an increase in basal cyclic GMP in Ca++.deprived tissue. Cyclic AMP levels were not significantly changed under any of these conditions. The addition of the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (0.1 mM), to ductus deferentes increased the amount of cyclic AMP about 50% and that of cyclic GMP about 2-fold. The latter effect also depended on the presence of Ca++. I-Methyl-3-isobutylxanthine (0.1 mM) increased cyclic GMP and cyclic AMP levels in slices of rat submaxillary glands. Methacholine increased cyclic GMP if added in the presence of methyl isobutylxanthine. Cyclic GMP control levels and the effect of methyl isobutylxanthine were unchanged by Ca + + omission, but the effect of methacholine was abolished.These findings indicate that calcium ions are important for the control of cyclic GMP levels in these tissues.The role of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) as an intracellular mediator in the action of various hormones has been well established (1). Hormones that increase cyclic AMP levels in intact cells can generally be shown to cause an increase in adenylate cyclase activity when added to broken cell preparations (1). While the physiological role of guanosine 3': 5'-cyclic monophosphate (cyclic GMP) is still unclear, the concentration of this nucleotide is increased by cholinergic and other agents in many mammalian tissues (2).The enzyme catalyzing the formation of cyclic GMP from GTP, guanylate cyclase, has been found in both particulate and high-speed supernatant fractions in many tissues (3). Neither of the forms of guanylate cyclase has consistently been affected in cell-free systems by agents that cause an increase in cyclic GMP levels in intact cells. Therefore, we have considered the possibility that the increase in intracellular cyclic GMP concentration in response to acetylcholine Abbreviation: SC-2964, 1-methyl-3-isobutylxanthine. * Present address: Department of Pharmacology, University of Heidelberg, Heidelberg, Germany.t To whom reprint requests should be sent. and other agents might be secondary to altered ion concentrations at the location of guanylate cyclase. The results presented in this paper show that calcium ions are involved in the regulation of cyclic GMP levels by cholinergic and other agents and that Ca++ may also be involved in the regulation of cyclic GMP formation under basal conditions. MATERIALS AND METHODSMaterials and methods u...

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“…Lymphocytes show an increased permeability to Ca2+ almost immediately after their initial contact with phytohaemagglutinin (Allwood et al, 1971;Whitney & Sutherland, 1972;Freedman et al, 1975) and they can be induced to grow and divide if their intracellular Ca2+ concentration is raised by using the ionophore A23187 (Maino et al, 1974). It thus seems likely that interaction of phytohaemagglutinin or other mitogens with their receptors leads to an increase in cell-surface permeability to Ca2+, and that the resulting rise in the intracellular Ca2+ concentration provides the initial stimulus to cell transformation .…”

mentioning

confidence: 99%

A comparison of the effects of phytohaemagglutinin and of calcium ionophore A23187 on the metabolism of glycerolipids in small lymphocytes

Allan¹,

Michell²

1977

Biochemical Journal

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1. The effects of phytohaemagglutinin and of a Ca2+ ionophore (A23 187) on glycerolipid metabolism in lymphocytes from pig lymph nodes were compared (a) by studying the incorporation of [32P] Phytohaemagglutinin only stimulated 32p incorporation into phosphatidylinositol and, to a slight extent, phosphatidate. Removal of most of the extracellular Ca2+ somewhat decreased this response. 3. lonophore A23187 stimulated the labellingofphosphatidateand phosphatidylinositol with 32p to a much greater extent than did phytohaemagglutinin: the increase in phosphatidate labelling, but not that of phosphatidylinositol, was almost abolished by the removal of extracellular Ca2+. 4. The combined effects of phytohaemagglutinin and ionophore appeared to be additive, rather than synergistic. 5. Treatment with ionophore A23187 somewhat decreased the total incorporation of [3H]glycerol into glycerolipids, possibly because it lowered cell ATP content. In these experiments di-and tri-acylglycerol behaved anomalously, triacylglycerol labelling being suppressed completely, whereas that of diacylglycerol was enhanced. The pulse-chase results revealed that triacylglycerol was converted into diacylglycerol in the ionophore-treated cells, and the availability of this diacylglycerol probably led to the enhanced labelling of phosphatidate and phosphatidylinositol in these cells. 6. Thus an increase in intracellular Ca2+ concentration appeared to have three effects on glycerolipid metabolism: (a) slight inhibition of some metabolic step preceding phosphatidate synthesis, (b) inhibition of diacylglycerol acyltransferase and (c) activation of a triacylglycerol lipase. 7. In contrast, it seems likely that the only effect of phytohaemagglutinin is to stimulate phosphatidylinositol breakdown. 8. Pig polymorphonuclear leucocytes treated with ionophore A23187 showed metabolic changes that were similar to those demonstrated with lymphocytes. 9. A possible similarity is suggested between Ca2+-stimulated triacylglycerol lipase in lymphocytes and polymorphonuclear leucocytes and previous observations of enhanced triacylglyerol metabolism in stimulated cells whose metabolic functions involve membrane fusion.

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Enhanced uptake of calcium by transforming lymphocytes

Cited by 152 publications

References 18 publications

Modulation of lymphocyte mitogenesis.

Modulation of lymphocyte mitogenesis.

The Importance of Calcium Ions for the Regulation of Guanosine 3′:5′-Cyclic Monophosphate Levels

A comparison of the effects of phytohaemagglutinin and of calcium ionophore A23187 on the metabolism of glycerolipids in small lymphocytes

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