Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypothalamic regulatory peptides bind to specific receptors on target cells in the pituitary and control secretion. They in turn can be regulated at the pituitary level by steroid and peptide modulators. Affinity cytochemical techniques are important tools for the identification of specific target binding sites for these regulatory peptides. This presentation reviews the work in which potent, biotinylated ligands of gonadotropin releasing hormone (bio-GnRH), corticotropin releasing hormone (bio-CRH), and arginine vasopressin (bio-AVP) were applied to study the target cell responses. Bio-GnRH, bio-CRH, and bio-AVP bind to membrane receptors on specific anterior pituitary cells. Dual labeling for either gonadotropin or adrenocorticotropin (ACTH) antigens further identified the target cells. After 1-3 minutes, the label was in patches or capped on the surface. After 3 minutes, it was internalized in small vesicles and sent to receptosomes and vacuoles in the Golgi complex. Eventually the biotinylated peptides, or a metabolite, was found in the lysosomes (multivesicular bodies) and a subpopulation of secretory granules. The route and rate of uptake was similar to that described for the classical receptor-mediated endocytosis process. In contrast, intermediate lobe corticotropes internalized the bio-CRH in less than 1 minute. The route through the Golgi complex appeared to be bypassed. Instead the labeled peptide was in vesicles, on the membranes of scattered vacuoles, and in multivesicular bodies. Modulation of ligand binding by steroids showed that changes in receptor numbers correlated with changes in the number of cells that bound the ligand. In male rats, dihydrotestosterone reduced the percentage of GnRH-bound cells by 50%. Most of the reduction appeared in cells that stored luteinizing hormone (LH) antigens. In diestrous female rats, estradiol increased the percentage of bio-GnRH-bound cells. However, the steroid decreased the percentage of GnRH-bound cells in cells from proestrous rats. Glucocorticoids decreased the percentage of CRH-bound corticotropes in as little as 10 minutes. Potentiation of secretion by these ligands was correlated with increases in the percentage of ligand-bound cells. AVP pretreatment of corticotropes increased the percentage of cells that bound bio-CRH. It also increased the rate of receptor-mediated endocytosis of CRH and changed the route so that the Golgi complex was bypassed. This effect could be mimicked by activation of its second messengers (calcium and protein kinase C). Similarly, CRH pretreatment increased the percentage of corticotropes that bound AVP. Thyrotropin releasing hormone (TRH) pretreatment also increased the percentage of thyrotropes that bound AVP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypothalamic regulatory peptides and their receptors: cytochemical studies of their role in regulation at the adenohypophyseal level. 166 66

The present study examines the effect of reduction of protein kinase C (PKC) activity, as induced by either phorbol ester (PMA) down-regulation or staurosporine inhibition, on the secretion of ACTH from cultured anterior pituitary (AP) cells. Short-term (3 h) exposure of cells to 5 nM PMA resulted in almost complete desensitization to both PMA and vasopressin (AVP), while there was only a minor incidence on the effect of corticotropin-releasing factor (CRF). In contrast, long-term (12-24 h) exposure of cells to PMA, as well as pretreatment with staurosporine, dramatically reduced the stimulatory influence of CRF. This was shown not to be due to a decline in ACTH cells' stores, nor to the toxicity of phorbol ester or to a negative autofeedback of ACTH. Pretreatment of corticotrophs with PMA failed to dampen the CRF-induced cyclic AMP formation, while it caused a decline in the effects of forskolin and 8-bromoadenosine cyclic AMP. Stimulated ACTH secretion subsequent to either veratridine- or high K(+)-induced cell depolarization was likewise decreased. We conclude that in corticotrophs the stimulatory action of not only AVP, but also of that of CRF on ACTH secretion strongly relies on PKC activity. In the case of CRF, however, this may not be a primary consequence of receptor occupation, as evidence suggests an indirect relationship which may involve PKC regulation of Ca2+ channels and/or the ion's intracellular messenger function.
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PMID:Inhibition of protein kinase C activity in cultured pituitary cells attenuates both cyclic AMP-independent and -dependent secretion of ACTH. 166 63

Human fetal adrenals are very active in steroid production. They make large amounts of dehydroepiandrosterone sulfate which is further converted to estrogens in placenta. Fetal adrenals cannot make cortisol efficiently from cholesterol or pregnenolone, but they can convert progesterone to cortisol. To clarify the molecular basis of the very low activity of 3 beta-hydroxy-5-ene steroid dehydrogenase (3 beta HSD) in human fetal adrenals we studied the expression of 3 beta HSD gene in fetal adrenals in vivo and in culture conditions. Human adult adrenals, placenta and a testicular Leydig cell tumor clearly expressed 3 beta HSD gene when studied by Northern blotting, but fetal adrenals and ovaries had no detectable 3 beta HSD mRNA by this method. Polymerase chain reaction analysis of cDNA samples derived from different human tissues revealed 3 beta HSD gene expression in placenta, adult adrenal and adult ovarian granulosa cells after 25 cycles of amplification. Fetal adrenal samples became positive only after additional amplification cycles, which verifies the very low expression of 3 beta HSD gene in fetal adrenals. In cell culture conditions both ACTH and a protein kinase C regulator 12-O-tetradecanoyl phorbol-13-acetate induced 3 beta HSD gene expression. We conclude: 1) the very low activity of 3 beta HSD in human fetal adrenals is due to the low expression of this gene; 2) both cAMP and protein kinase C-dependent mechanisms regulate 3 beta HSD gene expression in adrenocortical cells.
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PMID:Low expression of 3 beta-hydroxy-5-ene steroid dehydrogenase gene in human fetal adrenals in vivo; adrenocorticotropin and protein kinase C-dependent regulation in adrenocortical cultures. 184 66

The cellular mechanisms for aldosterone biosynthesis are incompletely understood. Although the enzymes involved are now well characterized, the dynamics of aldosterone secretion in a variety of rat adrenal preparations are not consistent with the concept that freshly synthesized corticosterone is an important intermediate. In whole glomerulosa tissue preparations, aldosterone is more readily formed from endogenous precursors than from an added radioactive precursor, such as [3H]pregnenolone, and in the in situ perfused gland preparation, aldosterone responses to stimulation, for example by ACTH, are significantly more rapid than those of corticosterone, suggesting a tissue source of steroid substrate for aldosterone production other than corticosterone. The only steroid which is stored in rat adrenal glomerulosa tissue to any extent is 18-hydroxydeoxycorticosterone (18-OH-DOC), and this pool has been located in plasma membrane fractions. It is lost on preparation of collagenase dispersed glomerulosa cells. Since dispersed glomerulosa cell preparations produce significantly less aldosterone, relative to corticosterone, than incubated intact whole glomerulosa, it is plausible that this tissue pool (which is not found in the inner zones) is the immediate precursor for aldosterone formation. Further evidence shows that trypsin, which stimulates aldosterone (and 18-hydroxycorticosterone) production in rat intact glomerulosa tissue, but not in dispersed cells, stimulates translocation of protein kinase C to the plasma membrane. It is plausible that one function of protein kinase C in the rat adrenal zona glomerulosa is to mobilize membrane sequestered 18-OH-DOC for conversion to aldosterone.
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PMID:The biosynthesis of aldosterone. 195 74

The present study was aimed at investigating the effect of protein kinase C (PKC) activation on CRF receptor function of proopiomelanocortin (POMC) cells in culture. Incubation of tissues with the phorbol ester PMA selectively potentiated corticotropin-releasing factor (CRF)-stimulated ACTH secretion and cyclic AMP formation of anterior pituitary (AP) cells, while, in sharp contrast, it failed to similarly affect intermediate pituitary (IP) cells and AtT-20 corticotrophs exposed to CRF. Unexpectedly, however, long-term treatment of cultures with PMA, which depletes cell stores of PKC, resulted in a similar dramatic attenuation of stimulated peptide release from both corticotrophs and melanotrophs, while being without significant effect on cyclic AMP production. Exposure of cells to PMA did not change either basal or CRF-enhanced levels of POMC mRNA. We conclude that activation of PKC fails to synergize with CRF-mediated signalling in IP and AtT-20 cells, although optimal CRF receptor expression requires the presence of a functional kinase C pathway, thus suggesting cross-talks between both messenger systems.
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PMID:Activation of protein kinase C differentially regulates corticotropin-releasing factor-stimulated peptide secretion and cyclic AMP formation of intermediate and anterior pituitary cells in culture. 196 31

The involvement of the calcium messenger system in the control of steroidogenesis in the rat and bovine adrenal cortex has been studied extensively. However the role of these second messengers in the control of human adrenocortical function is not established. This was therefore studied by incubating collagenase-dispersed human adrenocortical cells with the calcium ionophore A23187 and the protein kinase C activator phorbol 12-myristate 13-acetate (TPA). The effects of the calcium channel blocker verapamil on basal and stimulated steroidogenesis were also studied. Both TPA (1 pmol/l-10 mumol/l) and A23187 (1 nmol/l-10 mumol/l) caused a dose-dependent increase in cortisol, aldosterone and corticosterone production. Verapamil (10 mumol/l) inhibited the increase in aldosterone, corticosterone and cortisol produced in response to ACTH(1-24), potassium, and desacetyl-alpha MSH. Unlike previous results in the rat, these effects were not specific for aldosterone secretion. The results suggest that, as in other species, calcium mobilization and protein kinase C activation have a role in the control of steroidogenesis in the human adrenal cortex. However, in contrast to the rat, these mechanisms appear to be involved in the control of steroidogenesis in both the zona glomerulosa and inner zone cells.
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PMID:Control of steroidogenesis by the calcium messenger system in human adrenocortical cells. 201 56

We have reported previously that anterior pituitary cells released interleukin-6 (IL-6) and that this release was stimulated by lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or agents that increased intracellular cAMP concentrations. We now report that IL-1 stimulates IL-6 release from anterior pituitary cells in vitro. IL-1 alpha and IL-1 beta (0.04-25 ng/ml) significantly increased IL-6 release 3- to 4-fold in a concentration-related manner during 6-h incubations; however, there was no change in extracellular or intracellular cAMP concentrations. IL-1 alpha and IL-1 beta (10 ng/ml), vasoactive intestinal peptide (VIP, 500 nM), prostaglandin E2 (PGE2, 1 microM), and LPS (1 ng/ml) stimulated IL-6 release to a similar degree. In the presence of VIP and PGE2, IL-1 alpha and IL-1 beta increased IL-6 release without any apparent further change in extracellular or intracellular cAMP. Conversely, LPS did not increase cAMP concentrations, and IL-1 did not significantly increase IL-6 release in the presence of LPS. The preexposure of anterior pituitary cells to 1 microM PMA caused the apparent down-regulation of protein kinase C activity because 100 nM PMA was no longer effective to stimulate IL-6 release; however, the ability of IL-1 alpha, IL-1 beta, PGE2, or LPS to stimulate IL-6 release was not altered. In addition, IL-1 alpha and IL-1 beta stimulated IL-6 release in the presence of maximally stimulative concentrations of PMA. The synthetic glucocorticoid dexamethasone (10 nM) significantly inhibited IL-6 release induced by IL-1 alpha, IL-1 beta, or LPS. The separation of anterior pituitary cells on unit gravity BSA gradients generated fractions of IL-6-producing cells that were inducible by LPS and IL-1 beta and separate from the PRL-, ACTH-, GH-, or LH-producing cell fractions. These data suggest that IL-1 stimulates IL-6 release from a subpopulation of anterior pituitary cells via a glucocorticoid-sensitive and non-cAMP-mediated pathway that is different from those pathways used by VIP, PGE2, and PMA.
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PMID:Interleukin-1 stimulates interleukin-6 release from rat anterior pituitary cells in vitro. 203 55

Effects of ACTH on the production of diacylglycerol (DAG) and translocation of protein kinase C were studied in primary cultures of calf adrenal glomerulosa cells. To study DAG production two different labeling protocols were used: (a) cells were prelabeled for 3 days with [2-3H]glycerol before ACTH addition; (b) ACTH and [2-3H]glycerol were added simultaneously to cells. In both cases, ACTH provoked rapid increases in the labeling of DAG which were maximal in 2 min, dose-dependent, and paralleled by increases in DAG mass. ACTH also increased the labeling of total glycerolipids including phosphatidic acid (PA), phosphatidylinositol, phosphatidylethanolamine, phosphatidylcholine and triacylglycerol. In both labeling protocols, the rates of increase in the labeling of DAG and PA were greater than those of other glycerolipids. Our results indicate that ACTH rapidly increases DAG, at least partly by stimulating the de novo synthesis of PA. In addition, we found that ACTH, like phorbol esters, stimulated the apparent translocation of immunoreactive protein kinase C from the cytosol to the membrane fraction.
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PMID:ACTH increases de novo synthesis of diacylglycerol and translocates protein kinase C in primary cultures of calf adrenal glomerulosa cells. 215 56

The effects of corticotropin (ACTH) and tetradecanoyl phorbol acetate (TPA) on cholesterol ester hydrolase, intracellular cholesteryl ester concentration and steroid hormone formation were studied in mouse adrenal tumor cells (Y-1) in monolayer culture. Cholesterol ester hydrolase activity increased about 2-fold during 7 min incubation with ACTH, dibutyryl 3',5'-cyclic AMP (dbcAMP) and TPA at maximally effective concentrations; whereas, incubation with phorbol monoacetate had no effect. Long-term exposure to ACTH and dbcAMP markedly lowered intracellular cholesteryl [3H]-oleate concentration and highly increased steroid hormone output, while TPA treatment resulted in lowering cholesteryl [3H]-oleate content without affecting steroid hormone formation. Calcium activated phospholipid-dependent protein kinase C was detected in Y-1 cell cytosol. It is concluded that the mouse adrenal tumor cells in monolayer culture respond to ACTH in a fashion similar to normal adrenocortical cells; whereas, the response to the phorbol ester TPA (possibly mediated through protein kinase C) involves activation of cholesterol ester hydrolase and cholesteryl ester depletion, however, without affecting steroid hormone secretion.
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PMID:Hormone-sensitive cholesterol ester hydrolase in adrenal tumor cells: activation by corticotropin and tetradecanoyl phorbol acetate. 216 Aug 87

The present study was aimed at evaluating the capacity of anterior pituitary cells from neonatal rats to bind arginine vasopressin (AVP) and show AVP-receptor-mediated signal transmission. We found that in cultures of pituitary cells of 10-day-old pups, in contrast to cultures of cells of adults, AVP was unable to trigger sustained adrenocorticotropin (ACTH) secretion and, in addition, was also less potent in synergizing with the effect of corticotropin-releasing factor (CRF) on both ACTH output and cyclic AMP formation. Binding studies revealed the existence of a much lower number of AVP receptor sites in membranes of neonatal pituitary gland than in those of adult tissue (32.3 +/- 9.0 and 137.6 +/- 6.2 fmol/mg protein, respectively), although the binding of agonists and the apparent molecular weight (Mr about 120,000) of the receptors were similar. Activation by phorbol ester PMA of protein kinase C, a messenger involved in AVP action, resulted in a dose-related enhancement of ACTH secretion that was 2-3 times smaller for immature corticotrophs than for mature ones. Importantly, PMA treatment allowed AVP to significantly stimulate ACTH secretion from neonatal cells, while it failed to similarly affect AVP-evoked hormone output from adult tissue. Our results indicate that pituitary corticotrophs of rat pups fail to properly transduce AVP-receptor-mediated signalling and, thereby, suggest an explanation for the postnatal 'stress nonresponsive period'.
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PMID:The vasopressin receptor system in the neonatal pituitary gland: evidence for reduced binding capacity and signal transmission. 216 16


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