Lithium-induced reduction in intracellular inositol supply in cholinergically stimulated parotid gland

Downes, C P; Stone, Margaret

doi:10.1042/bj2340199

Cited by 127 publications

(74 citation statements)

References 31 publications

(22 reference statements)

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“…Thus, PtdIns(4,5)P 2 not only recovers to basal levels with a shorter half-time but also recovers by Ͼ60% before PtdIns(4)P recovery commences. Such protection of PtdIns(4,5)P 2 is in accord with studies in other systems (24,38,39) and suggests that substrate availability and product inhibition are unlikely to be the only factors governing the supply of PtdIns(4,5)P 2 . Thus, mechanisms exist that coordinate polyphosphoinositide synthesis in accordance with demand, and the current data indicate that these mechanisms are of relevance in intact cells.…”

Section: Discussionsupporting

confidence: 72%

Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

Willars

Nahorski

Challiss

1998

Journal of Biological Chemistry

164

177

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In this study we have quantitatively assessed the basal turnover of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) and M 3 -muscarinic receptor-mediated changes in phosphoinositides in the human neuroblastoma cell line, SH-SY5Y. We demonstrate that the polyphosphoinositides represent a minor fraction of the total cellular phosphoinositide pool and that in addition to rapid, sustained increases in [ 3 H]inositol phosphates dependent upon the extent of receptor activation by carbachol, there are equally rapid and sustained reductions in the levels of polyphosphoinositides. Compared with phosphatidylinositol 4-phosphate (PtdIns(4)P), PtdIns(4,5)P 2 was reduced with less potency by carbachol and recovered faster following agonist removal suggesting protection of PtdIns(4,5)P 2 at the expense of PtdIns(4)P and indicating specific regulatory mechanism(s). This does not involve a pertussis toxin-sensitive G-protein regulation of PtdIns(4)P 5-kinase. Using wortmannin to inhibit PtdIns 4-kinase activity, we demonstrate that the immediate consequence of blocking the supply of PtdIns(4)P (and therefore PtdIns(4,5)P 2 ) is a failure of agonist-mediated phosphoinositide and Ca 2؉ signaling. The use of wortmannin also indicated that PtdIns is not a substrate for receptor-activated phospholipase C and that 15% of the basal level of PtdIns(4,5)P 2 is in an agonist-insensitive pool. We estimate that the agonist-sensitive pool of PtdIns(4,5)P 2 turns over every 5 s (0.23 fmol/cell/min) during sustained receptor activation by a maximally effective concentration of carbachol. Immediately following agonist addition, PtdIns(4,5)P 2 is consumed >3 times faster (0.76 fmol/cell/min) than during sustained receptor activation which represents, therefore, utilization by a partially desensitized receptor. These data indicate that resynthesis of PtdIns(4,5)P 2 is required to allow full early and sustained phases of receptor signaling. Despite the critical dependence of phosphoinositide and Ca 2؉ signaling on PtdIns(4,5)P 2 resynthesis, we find no evidence that this rate resynthesis is limiting for agonist-mediated responses.

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Section: Discussionsupporting

confidence: 72%

Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

Willars

Nahorski

Challiss

1998

Journal of Biological Chemistry

164

177

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“…Our observation that calcium mobilization is apparently normal during superfusion with lithium-containing solutions may support this possibility since lithium supports Na+-H+ exchange in some cell types (Boron, McCormick & Roos, 1981;Kinsella & Aronson, 1981;Ellis & McLeod, 1985). This result must, however, be interpreted with caution since lithium inhibits the metabolic recycling of inositol polyphosphates (Downes & Stone, 1986) which are extremely important mediators of calcium mobilization and influx (Streb, Irvine, Berridge & Schulz, 1983;Morris, Gallacher, Irvine & Petersen, 1987), and therefore may interfere with [Ca2+]i regulation.…”

Section: Effects Of Removing External Sodiumsupporting

confidence: 44%

The effects of removing external sodium upon the control of potassium (86Rb+) permeability in the isolated human sweat gland

Wilson

Bovell²,

Elder³

et al. 1990

Experimental Physiology

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SUMMARYThe changes in cytoplasmic free calcium ([Ca2+]i) which occur in isolated human sweat glands during cholinergic stimulation have been studied indirectly by monitoring potassium permeability. The acetylcholine-evoked permeability increase normally consists of transient and sustained phases which are attributed to the mobilization of intracellular calcium stores and to calcium influx respectively. Such consistent responses to acetylcholine could not be obtained during superfusion with bicarbonate-free, HEPES-buffered solutions. The human sweat gland in vitro therefore appears to have a strict requirement for bicarbonate. The sustained component of the response was not affected by total removal of external sodium, suggesting that calcium influx does not occur via a sodium-dependent system. The transient component, however, was abolished when external sodium was replaced by N-methyl-Dglucammonium (NMDG+). It therefore appears that secretagogue-evoked mobilization of cytoplasmic calcium is dependent, in some way, upon external sodium. This dependence is not, however, absolute as the response was essentially normal when sodium was replaced by lithium.

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“…A direct role of this activity in the LiCI potentiation of the TNF cytotoxicity is unlikely in view of the following observations. The effect of LiCl on TNF cytotoxicity was not reversed with 20 mM extracellular inositol (data not shown), which reverses the LiCl-induced reduction of phosphatidylinositol formation in cholinergically stimulated parotid glands (18). NaF also inhibits inositol-1-phosphatase (19) but protected against TNF-mediated cytotoxicity at a concentration of 500 ,uM (data not shown).…”

Section: Resultsmentioning

confidence: 97%

Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo.

Beyaert

Vanhaesebroeck

Suffys

et al. 1989

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

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Tumor necrosis factor (TNF) is cytotoxic for several transformed cell lines in vitro. In the presence of LiCI, the murine fibrosarcoma cell lines L929 and WEHI 164 done 13 became >10 times more sensitive to TNF-mediated cytotoxicity. The human tumor cell lines BT20 and HeLa D98/AH2 were also responsive to the cytotoxicity-enhancing effect of LiCI. Other monovalent or divalent cations did not affect TNF-mediated cytotoxicity. The potentiating effect of LiCI on TNF cytotoxicity was largely independent of transcription, and LiCl could be added to the cells as early as 2 hr before or as late as 4 hr after TNF without loss of effectiveness. The mechanism by which LiCI increases the cytotoxic response seems to differ from the sensitizing effect of actinomycin D or interferon y, since the latter treatments overcame TNF resistance of several cell lines, whereas LiCl did not. Evidence is presented that LiCl acts, either directly or indirectly, via the TNF-activated phospholipase A2 pathway. In nude mice, a combination ofTNF and LiCl led to hemorrhagic necrosis and growth inhibition of L929 tumors, whereas little effect was observed when TNF was administered alone. HeLa D98/AH2 tumors also were sensitive to the potentiating effect of LiCl in vivo. We conclude that LiCl enhances the effectiveness of TNF in vitro and in vivo, results that may have therapeutic implications.Tumor necrosis factor (TNF) is a cytokine that was originally identified in the sera of mice that had been primed with bacillus Calmette-Guerin and challenged with endotoxin. When injected into mice bearing methylcholanthreneinduced sarcomas, TNF causes hemorrhagic necrosis of the tumor (1). In vitro, TNF exerts cytostatic and cytotoxic activity against a wide range of human and murine tumor cell lines, although it has little or no antiproliferative activity on nontransformed cell lines (2, 3). However, not all tumor cells are sensitive to TNF-mediated cytotoxicity. The molecular mechanism for this difference in response still remains largely unknown. Recently, a serine-type protease was shown to be involved in TNF-mediated cytotoxicity (4). Furthermore, there is ample evidence for an activation of a phospholipase A2 (PLA2) activity (5, 6). In addition to its cytotoxic effect on transformed cells, TNF mediates a variety of other biological activities on various cell types, both in vivo and in vitro (7).In our efforts to understand the mechanism of action of TNF on malignant cells, we also evaluated a possible involvement of phospholipase C activity. In these experiments, we tested whether LiCl, which is known to inhibit inositol-1-phosphatase (8), would interfere with specific tumor cell killing by TNF. Surprisingly, we found instead that LiCl potentiated TNF-mediated cytotoxicity in vitro almost to a similar extent as has been shown before for actinomycin D (ActD) and cycloheximide (2) and, more physiologically, for interferon (IFN) (3, 9). Moreover, this LiCl-specific TNF potentiation can be extended to the in vivo antitumor action of TNF. Elsewh...

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Lithium-induced reduction in intracellular inositol supply in cholinergically stimulated parotid gland

Cited by 127 publications

References 31 publications

Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

Differential Regulation of Muscarinic Acetylcholine Receptor-sensitive Polyphosphoinositide Pools and Consequences for Signaling in Human Neuroblastoma Cells

The effects of removing external sodium upon the control of potassium (86Rb+) permeability in the isolated human sweat gland

Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo.

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