Influence of phorbol esters, and diacylglycerol kinase and lipase inhibitors on noradrenaline release and phosphoinositide hydrolysis in chromaffin cells

J. Alison Jones, P. J. Owen, M. R. Boarder

Research output: Contribution to journalArticle

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Abstract

1. We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59 022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism. 2. TPA (1 nM to 1 μM) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (-)-202 791 and potentiated by the channel enhancer (+)-202 791. 3. R 59 022 enhanced noradrenaline efflux at 30 and 50 μM, while the lipase inhibitor RG 80267 failed to elicit release. 4. Neither R 59 022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K+-stimulated release. 5. Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxy TPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24h TPA treatment. 6. Neither R 59 022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation. 7. Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.

Original languageEnglish
Pages (from-to)521-526
Number of pages6
JournalBritish Journal of Pharmacology
Volume101
Issue number3
DOIs
Publication statusPublished - 9 Nov 1990
Externally publishedYes

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Diacylglycerol Kinase
R 59022
Chromaffin Cells
Inositol Phosphates
Lipoprotein Lipase
Phorbol Esters
Phosphatidylinositols
Norepinephrine
Acetates
Hydrolysis
Bradykinin
Protein Kinase C
Histamine Release
Diglycerides
Calcium Channel Blockers
Type C Phospholipases
Lipase
Nicotine
Histamine
Catecholamines

Cite this

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abstract = "1. We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59 022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism. 2. TPA (1 nM to 1 μM) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (-)-202 791 and potentiated by the channel enhancer (+)-202 791. 3. R 59 022 enhanced noradrenaline efflux at 30 and 50 μM, while the lipase inhibitor RG 80267 failed to elicit release. 4. Neither R 59 022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K+-stimulated release. 5. Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxy TPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24h TPA treatment. 6. Neither R 59 022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation. 7. Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.",
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Influence of phorbol esters, and diacylglycerol kinase and lipase inhibitors on noradrenaline release and phosphoinositide hydrolysis in chromaffin cells. / Alison Jones, J.; Owen, P. J.; Boarder, M. R.

In: British Journal of Pharmacology, Vol. 101, No. 3, 09.11.1990, p. 521-526.

Research output: Contribution to journalArticle

TY - JOUR

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AB - 1. We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59 022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism. 2. TPA (1 nM to 1 μM) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (-)-202 791 and potentiated by the channel enhancer (+)-202 791. 3. R 59 022 enhanced noradrenaline efflux at 30 and 50 μM, while the lipase inhibitor RG 80267 failed to elicit release. 4. Neither R 59 022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K+-stimulated release. 5. Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxy TPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24h TPA treatment. 6. Neither R 59 022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation. 7. Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.

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