Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies of the effects of angiotensin II (All), alone or in combination with activators of the protein kinase. A signalling pathway, have yielded inconsistent findings on the expression of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD and 17 alpha-hydroxylase cytochrome P450 (P450c17) as well as the corresponding responses on steroid secretory products in human adrenocortical cells. We have used the human adrenocortical carcinoma H295R cell further to evaluate this question, as well as to determine the role of protein kinase C in each of these responses to All. Treatment with All alone resulted in a marked increase in aldosterone secretion and a significant increase in cortisol secretion (1-8-fold). The increased formation of 17-hydroxysteroids was accompanied by an increased level of P450c17 mRNA and activity. Increases in 3 beta-HSD expression were also seen at the level of mRNA and to a lesser extent, at the level of activity. Because of the comparatively low basal 17 alpha-hydroxylase and high basal 3 beta-HSD activities of H295R cells, however, the overall effect of All treatment was actually a rise in the 17 alpha-hydroxylase/3 beta-HSD activity ratio, so resulting in increased formation of 17 alpha-hydroxysteroids such as cortisol. While treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) reproduced the effect of All on 3 beta-HSD expression, TPA failed to reproduce the effects of All on P450c17 because it caused a marked decrease in P450c17 expression. Thus the stimulatory effect of All on P450c17 expression, unlike that on 3 beta-HSD expression, was not mediated by protein kinase C but, like the action of K, was probably mediated via the Ca2+ signalling pathway. Treatment with forskolin resulted in a dramatic increase in both cortisol and dehydroepiandrosterone (DHEA) secretion together with increases in expression of 3 beta-HSD and P450c17 as measured at the level of mRNA and activity. Consistent with the increase in 17 alpha-hydroxysteroid formation, the effect on P450c17 expression was greater than that on 3 beta-HSD at the level of activity, so a larger 17 alpha-hydroxylase/3 beta-HSD activity ratio was achieved. Cotreatment with forskolin and All, however, resulted in a dose-dependent reduction in cortisol and DHEA secretion concomitant with a marked attenuation of 3 beta-HSD and P450c17 expression. While forskolin-induced expression of 3 beta-HSD was not further increased at the level of mRNA by cotreatment with All, additivity was observed as the level of activity changed. Thus All cotreatment resulted in a marked reduction in the forskolin-induced increase in the 17 alpha-hydroxylase/3 beta-HSD activity ratio, and so 17 alpha-hydroxysteroid synthesis was attenuated. The effect of All cotreatment on changes in forskolin-induced 3 beta-HSD activity was blocked by the All type 1 (AT1) antagonist DuP753 (Losartan), confirming the involvement of the AT1 receptor-linked phospholipase C in activating protein kinase C.
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PMID:Regulation of 3 beta-hydroxysteroid dehydrogenase expression in human adrenocortical H295R cells. 894

Previous studies of human adrenocortical cells have given inconsistent findings concerning the effects of angiotensin II (AII) alone or in combination with activators of the protein kinase A-signaling pathway on expression of cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha-hydroxylase cytochrome P450 (P450c17), and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), as well as the corresponding effects on adrenocortical cell steroid secretory products. We have used the human adrenocortical carcinoma H295R cell to evaluate further this question and determine the role of protein kinase C in each of these responses to AII. Treatment with AII alone (10 nmol/L, 48 h) resulted in a significant increase in cortisol production (1.8-fold), as well as a much greater effect on aldosterone production. This increased formation of 17 alpha-hydroxysteroids was accompanied by increased expression of P450c17 as determined at the level of messenger RNA (mRNA) and enzyme activity. Similar increases in expression of P450scc were observed at the level of mRNA. Increases in 3 beta-HSD expression were also seen at the level of mRNA and, to a lesser extent, at the level of enzyme activity. Because of the comparatively low basal 17 alpha-hydroxylase and high basal 3 beta-HSD activity of H295R cells, however, the overall effect of AII treatment was actually a rise in the 17 alpha-hydroxylase/3 beta-HSD activity ratio, resulting in increased formation of 17 alpha-hydroxysteroids such as cortisol. Whereas treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) reproduced the effect of AII on 3 beta-HSD expression, TPA failed to reproduce the effects of AII on P450c17 and P450scc and even resulted in a marked decrease in expression of P450c17. Thus, the stimulatory effect of AII alone on P450c17 expression was not mediated via protein kinase C but, like the action of K+, was probably mediated via the Ca(2+)-signaling pathway. Treatment with forskolin (10 mumol/L, 48 h) resulted in a dramatic increase in both cortisol and dehydroepiandrosterone production together with increases in expression of P450c17, P450scc, and 3 beta-HSD as measured at the level of mRNA and activity. Consistent with the increase in 17 alpha-hydroxysteroid formation, the effect on 17 alpha-hydroxylase expression was greater than that on 3 beta-HSD at the level of enzyme activity, so a larger 17 alpha-hydroxylase/3 beta-HSD activity ratio was achieved. Cotreatment with forskolin and AII, however, resulted in a dose-dependent reduction in cortisol and DHEA production concomitant with a marked attenuation of P450scc and P450c17 expression. Although forskolin-induced expression of 3 beta-HSD was not further increased at the level of mRNA by cotreatment with AII, additivity was observed at the level of changes in enzyme activity. Thus, AII cotreatment resulted in a marked reduction of the forskolin-induced increase in 17 alpha-hydroxylase/3 beta-HSD activity ratio, and so, 17 alpha-hydroxysteroid synthesis was attenuated. These effects of AII cotreatment on expression of P450c17 and P450scc were reproduced by cotreatment with TPA (10 nmol/L), suggesting the involvement of protein kinase C in these attenuative responses. Furthermore, the effect of AII cotreatment on changes in forskolin-induced 17 alpha-hydroxylase and 3 beta-HSD activities were blocked by the AII Type 1 (AT1) receptor antagonist DuP753 (Losartan), confirming the involvement of an AT1 receptor-linked phospholipase C in activating protein kinase C.
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PMID:Differential control of 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase expression in human adrenocortical H295R cells. 896 47

The purpose of this study was to investigate the mechanisms of action of pituitary adenylate cyclase-activating polypeptide (PACAP) in stimulating aldosterone production in two different models: bovine adrenal zona glomerulosa (ZG) cells in primary culture and the human adrenocortical carcinoma cell line H295R. PACAP binds to two major groups of receptors: type I, which prefers PACAP38 and PACAP27 over vasoactive intestinal peptide (VIP); and type II, which has approximately equal affinity for PACAP38, PACAP27, and VIP. The type I subclass comprises multiple splice variants that can be distinguished by their specificity to PACAP38 and PACAP27 in their activation of adenylate cyclase and phospholipase C. Type II PACAP/ VIP receptors couple only to AC. In bovine ZG cells, PACAP38 and PACAP27 stimulated aldosterone production in a dose-dependent manner, whereas VIP was ineffective. In H295R cells, PACAP38, PACAP27, and VIP dose-dependently stimulated aldosterone production with roughly the same ED50. In bovine ZG cells, PACAP38 and PACAP27 stimulated cAMP production with similar efficacy, whereas VIP had no effect. In H295R cells, all three peptides stimulated cAMP accumulation. PACAP38 and PACAP27 also activated PLC in bovine ZG cells as they induced an increase in Ins(1,4,5)Ps production. In H295R cells, neither of these peptides was able to stimulate IP turnover. These results indicate that PACAP stimulation of aldosterone production is mediated by the PVR1s or the PVR1hop splice variants of the type I PACAP-specific receptor subtype in bovine ZG cells, whereas only type II PACAP/VIP receptors seemed to occur in the human H295R cell line. In addition, PACAP-stimulated aldosterone production was inhibited by atrial natriuretic peptide in bovine and human adrenocortical cells, however not by the same mechanism. This further supports species-specific and/or cell type-specific signaling pathways for PACAP in the regulation of aldosterone production.
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PMID:Comparative effect of pituitary adenylate cyclase-activating polypeptide on aldosterone secretion in normal bovine and human tumorous adrenal cells. 900 87