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

The intracellular mechanisms of action of alpha-MSH in rat adrenocortical cells were examined. When rat adrenal capsule (largely glomerulosa) cells were stimulated with a range of concentrations of alpha-MSH there was significant stimulation of aldosterone secretion at 10(-10) mol/l, although cyclic AMP was not increased until high concentrations of alpha-MSH were used (10(-6) mol/l and above). However, cells incubated with ACTH showed an increase in aldosterone secretion at 10(-11) mol/l and levels of cyclic AMP were elevated at 10(-9) mol ACTH/l. When rat adrenal whole capsules were incubated with alpha-MSH, membrane-bound protein kinase C (PKC) activity was increased and cytosolic enzyme activity decreased, showing PKC activation. Stimulation with angiotensin II also induced translocation of PKC activity, but ACTH did not. When [3H]inositol-loaded glomerulosa cells were stimulated with alpha-MSH there was significant generation of [3H]inositol trisphosphate (IP3) at concentrations of alpha-MSH which stimulated secretion of aldosterone. Significantly increased levels of [3H]IP3 were also measured when loaded cells were exposed to angiotensin II. ACTH did not cause any significant stimulation of [3H]IP3 production at any concentration used. These results indicate that activation of PKC and phospholipase C is important in modulating the steroidogenic effect of alpha-MSH.
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PMID:Studies on the intracellular mechanism of action of alpha-melanocyte-stimulating hormone on rat adrenal zona glomerulosa. 132 51

When bovine adrenocortical cells from the zona fasciculata/reticularis (zfr) are maintained in primary culture, cortisol secretion in response to acute stimulation with ACTH and adrenaline (which activate adenylate cyclase) is seen to increase steadily over the first 48 h, while secretion in response to angiotensin II and acetylcholine (which activate phosphoinositidase C) shows an initial decline in the first 24 h and a recovery to maximum after 48 h. We have investigated whether these discrepant changes in cortisol secretory response to the different agonists are due to changes in formation of the associated second messengers (cAMP or inositol phosphates), or altered coupling of these second messenger signals to steroid secretion. Increases in steroid secretion in response to ACTH and adrenaline were paralleled by increased cAMP. Steroid secretion in response to exogenous 8-bromoadenosine 3':5'-cyclic monophosphate also increased steadily during this 48-h period. Thus increased responsiveness was due to both increased second messenger formation and increased coupling to the steroid secretory response. The decreased steroid secretory response to angiotensin and acetylcholine after 24 h, and subsequent recovery after 48 h in culture, were accompanied by an increased formation of phosphoinositols after 24 h and a further increase by 48 h. However, the steroid secretory response to a combination of calcium ionophore and the protein kinase C activator, phorbol 12-myristate 13-acetate, was reduced after 24 h and recovered by 48 h of culture. Fura-2-loaded cells also showed an increase in intracellular [Ca2+] after 24 h in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Further characterization of the steroidogenic responsiveness of purified zona fasciculata/reticularis cells from bovine adrenal cortex before and after primary culture: changing responsiveness to phosphoinositidase C agonists. 132 34

The present study involves the effects on corticotropin (ACTH) release of neuro- and thymoleptic tricyclic antidepressant compounds (TrcACs: chlorpromazine, promethazine, haloperidol, imipramine, amitriptyline) and their interactions with lysine-8-vasopressin (LVP) and corticosterone (B). As an in vitro model, 14-day monolayer pituitary cell cultures of Wistar rats were employed. The ACTH concentrations of the supernatant media were measured by radioimmunoassay. TrcACs augmented ACTH release; their combination with LVP, however, did not result in further stimulation; moreover, when combined with TrcACs + LVP, B did not inhibit, but rather paradoxically increased their ACTH-releasing action. As none of these phenomena were followed by relevant changes in intracellular cyclic adenosine monophosphate content, the mechanism of action may be proposed to involve a protein kinase C route.
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PMID:Central effects of tricyclic compounds on the endocrine system--an in vitro study. 132 50

Interactions between signal transducing systems may be important in the integrated control of cellular processes in basal and hormonally regulated cells. The cultured bovine adrenal fasciculata cell provides a model to study the interactions between the cAMP and calcium-sensitive phospholipid dependent protein kinase C. In this study, angiotensin II (A-II) and phorbol ester (PMA) potentiated the stimulatory actions of ACTH in a dose-dependent manner on cAMP production. At maximal concentrations, A-II and PMA also potentiated the effects of cholera toxin and forskolin on cAMP production. Both staurosporine, a protein kinase C inhibitor, and desensitization of protein kinase C by a 24-h pretreatment with PMA blunted the effect of PMA, but only partially inhibited (34%) the effect of A-II. Neither nifedipine, a specific calcium channel antagonist, nor pretreatment of cells with pertussis toxin modified the amplifying effects of A-II or PMA. In contrast, trifluoperazine, a calmodulin inhibitor, reduced the potentiating effect of A-II by about 35%, but association with staurosporine blunted its effects. Moreover, the steroidogenic effects of ACTH plus A-II were more than additive, but this synergism was blunted in the presence of both inhibitors. In conclusion, PMA and A-II potentiated agonist-induced cAMP production by bovine adrenal fasciculata cells. The data suggest that the effects of PMA were mediated exclusively by protein kinase C, whereas those of A-II were mediated by both protein kinase C and calmodulin.
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PMID:Angiotensin II potentiates agonist-induced 3',5'-cyclic adenosine monophosphate production by cultured bovine adrenal cells through protein kinase C and calmodulin pathways. 133 Apr 96

These studies were undertaken to evaluate the role of protein kinase C (PKC) in the regulation by arginine vasopressin (AVP) of adrenocorticotropin (ACTH) secretion from the ovine anterior pituitary. AVP caused the rapid translocation of PKC from the cytosol to the cell membrane in ovine anterior pituitary cells that was maximal at 5 min. This phenomenon, which is a known concomitant of C-kinase activation, was produced to a greater extent by phorbol 12-myristate 13-acetate (PMA) but not by corticotropin-releasing factor (CRF). To determine whether AVP activated corticotrope PKC, we assessed the ability of three different PKC inhibitors (H-7, sphingosine, and retinal) to modify basal, AVP-, PMA-, and CRF-stimulated ACTH release. In addition to inhibiting the in vitro activity of purified PKC, each compound also caused in vitro inhibition of the protein kinase A (PKA) catalytic subunit, indicating that none could be considered to be a specific inhibitor of PKC and the PKA catalytic subunit. As determined by the mean IC50 values required for the in vitro inhibition of PKC and the PKA catalytic subunit, sphingosine was judged to be the most selective and H-7 the least selective PKC inhibitor. A 4 h exposure to each inhibitor caused a dose-dependent increase in basal ACTH release and attenuation of both AVP- and PMA-stimulated ACTH release. H-7 and retinal, in concentrations that caused a 20-50% inhibition of PKA, also attenuated CRF-stimulated ACTH release; however, this effect was not observed with sphingosine in concentrations that caused only a 10-20% inhibition of PKA. We conclude that: (1) AVP causes the direct activation of PKC in the ovine anterior pituitary and that C kinase activation is important in mediating the effect of AVP on ACTH release; (2) the finding that inhibition of PKC elevates ACTH suggests that basal ACTH secretion is also partly regulated by PKC; (3) since CRF does not cause PKC translocation in ovine anterior pituitary cells, it is unlikely that PKC plays a physiological role in the action of CRF on the corticotrope; (4) the finding that H-7 and retinal attenuate CRF-stimulated ACTH secretion suggests that CRF activates PKA in corticotropes.
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PMID:Evidence that the stimulation by arginine vasopressin of the release of adrenocorticotropin from the ovine anterior pituitary involves the activation of protein kinase C. 133 7

The adrenal glomerulosa cell is a major site of action of angiotensin II (AII), which binds to AT1 receptors to stimulate phosphoinositide hydrolysis and Ca2+ mobilization, and the subsequent production of aldosterone. All also influences adrenal growth and proliferation and promotes thymidine incorporation in adrenocortical cells. In primary cultures of bovine glomerulosa cells, AII was found to induce the expression of several early growth response genes (c-fos, c-jun, JunB, and Krox 24). This effect of AII was dose-dependent and was blocked by [Sar1,IIe8] AII and the nonpeptide antagonist DuP 753, indicating that it is mediated by the AT1 subtype of the AII receptor. ACTH, which elevates cAMP in glomerulosa cells, was a relatively weak inducer of c-fos expression but was as potent as AII in stimulating the expression of JunB. ACTH did not further enhance the maximal effect of AII on c-fos expression. The role of the AII-induced cytoplasmic Ca2+ increase in generating the c-fos response was suggested by the ability of the Ca2+ ionophore ionomycin to induce c-fos expression. However, mobilization of intracellular Ca2+ by the Ca2+ ATPase inhibitor thapsigargin, as well as the stimulation of Ca2+ influx by depolarization with potassium, were less potent stimuli of c-fos expression. Omission of Ca2+ from the extracellular medium, which abolishes the plateau phase of the AII-induced Ca2+ signal without affecting the early increase due to Ca2+ mobilization, enhanced the early phase of the AII-induced c-fos response, indicating that Ca2+ also has an inhibitory effect on the early gene response. Activation of protein kinase C by phorbol 12-myristate, 13-acetate (PMA) also stimulated c-fos expression, but the combination of PMA and ionomycin did not further increase the c-fos response. Inhibition of protein kinase C by staurosporine, or its depletion by prolonged exposure to PMA, prevented the c-fos response to PMA but only partially inhibited the response to AII, suggesting the involvement of other factors in stimulus-transcription coupling from the AT1 receptor.
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PMID:Stimulation of early gene expression by angiotensin II in bovine adrenal glomerulosa cells: roles of calcium and protein kinase C. 133 25

We have demonstrated that the novel hypothalamic peptide pituitary adenylate cyclase-activating polypeptide (PACAP-38; 0.1-100 nmol/l) caused an increase in the release of GH, ACTH, LH and alpha-subunit and accumulation of intracellular cyclic AMP from dispersed rat anterior pituitary cells in static culture for 24 h. There were no significant effects on TSH or prolactin release over the same time-period. PACAP-38 (10 nmol/l) increased the release of GH by 1.3-fold (P less than 0.05), ACTH by 1.9-fold (P less than 0.05), LH by 3.5-fold (P less than 0.001) and alpha-subunit by 2.0-fold (P less than 0.005) and the accumulation of intracellular cyclic AMP by greater than 2-fold (P less than 0.001) after 24 h. However, the time-course for the effect of PACAP-38 (1 mmol/l) on hormone release and intracellular cyclic AMP levels showed a temporal dissociation. The effect of PACAP-38 on GH and ACTH levels did not reach significance until 24 h whereas the effect of PACAP-38 on LH and alpha-subunit release reached significance after 4 h implying a different mechanism of action for their release. To investigate the PACAP-induced secretion of LH and alpha-subunit further, we examined the effects of PACAP after down-regulation of protein kinase C (PKC). PACAP-38 at a dose maximal for the stimulation of LH and alpha-subunit release (10 nmol/l) added together with the PKC activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 0.1 mumol/l) had no greater effect on LH and alpha-subunit release than TPA alone over a 4 h incubation period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of a novel hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide, on pituitary hormone release in rats. 138 57

Neurotensin (NT), a hypothalamic peptide which is also contained in the chromaffin granules of adrenal medullary cells, did not affect either basal or ACTH-stimulated secretory activity of isolated rat zona glomerulosa (ZG) cells. Conversely, NT was found to exert a strong dose-dependent inhibitory effect on aldosterone response of ZG cells to their two main calcium-dependent secretagogues angiotensin-II and potassium. These findings suggest that NT may interfere with the angiotensin-II- or potassium-induced activation of protein kinase C, possibly by blunting the rise in the cytosolic calcium concentration.
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PMID:Neurotensin inhibits the stimulatory effect of angiotensin-II and potassium on aldosterone secretion by rat zona glomerulosa cells. 165 Jul 5

The maintenance of optimal steroidogenesis in adrenocortical cells primarily depends on the chronic action of ACTH to promote the synthesis of the various steroid metabolizing enzymes. In the steroidogenic pathway, the ratio of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) to 17 alpha-hydroxylase cytochrome P450 (P-450(17 alpha)) plays a key role in determining the final steroid products released by adrenal cells. The differences in these enzymes are particularly important when one considers the adrenal zones and the secretion of the zone-specific steroids. In the present study we have investigated the regulation of 3 beta HSD with regard to its enzyme activity, levels of protein and changes in specific mRNA encoding for this enzyme. Following eight days in primary culture, bovine adrenocortical (BAC) cells were found to respond to both ACTH and Bu2 cAMP by increased cortisol production. In addition, 3 beta HSD activity, enzyme protein and mRNA levels were increased in response to both factors. The increases varied from 2-fold for activity to 5-7 fold for mRNA. ACTH and Bu2cAMP also greatly increased P-450(17 alpha) from the near undetectable levels in control cells. In order to examine the possibility of differential regulation of these adrenal steroidogenic enzymes we determined the effects of angiotensin II (A-II) and transforming growth factor beta (TGF beta) on the levels of these enzymes. Both of these factors decreased the ACTH-stimulated levels of P-450(17 alpha) enzyme and mRNA to near nondetectable levels observed within control cells. In addition, these compounds inhibited the ACTH induction of 3 beta HSD. While the mechanism of TGF beta action is not clear, A-II probably is acting through protein kinase C. Indeed the protein kinase C activating phorbol ester, TPA, mimicked the inhibitory effects of A-II on 3 beta HSD and P450(17 alpha). It is important to point out, however, that the effects of A-II and TGF beta on P450(17 alpha) activity appeared more pronounced than their action of 3 beta HSD. This observation may relate to the relative stability of 3 beta HSD as compared to P450(17 alpha). Taken together these data indicate that, while A-II and TGF beta each decrease the levels of steroid-metabolizing enzymes, a differential regulation is observed in that P-450(17 alpha) protein and activity levels are much more sensitive to treatment with these factors.
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PMID:Regulation of 3 beta-hydroxysteroid dehydrogenase in adrenocortical cells: effects of angiotensin-II and transforming growth factor beta. 165 33

It is well known that the adrenal zona glomerulosa is transformed to zona fasciculata-reticularis in rats exposed chronically to ACTH. This model was used to study the intracellular distribution of protein kinase C, which is known to be involved in differentiation processes. Under basal conditions, in zona glomerulosa, 70, 23, and 7% of the protein kinase C was located in the cytosol, membrane and nuclear fractions, respectively. At 30 min after ACTH administration to rats, the protein kinase C content remained unchanged in the nuclear fraction, whereas that of the cytosolic fraction was decreased to 43% while in the membranes it was increased to 48%. After 2 days of ACTH treatment, we observed a significant increase, up to 25%, of protein kinase C in the nuclear fraction, a decrease to 47% in the cytosol, whereas the membrane fraction content had returned to its basal value. The intracellular distribution of inner zones was 17% in nuclear fraction, 47% in cytosol and 36% in membranes. ACTH treatments did not change these proportions. The total protein kinase C content of ACTH-treated groups was not different than that of their respective controls, in zona glomerulosa and in inner zones respectively. The cytosolic protein kinase C formed complexes with detergent-treated nuclei; this association was saturable, and could be measured by the ability of the kinase to bind [3H]PDBu ([20(n)-3H]phorbol-12,13-dibutyrate). The number of nuclear 'acceptor sites' thus measured was calculated to be 5245 fmol/mg DNA in the zona glomerulosa; this did not change significantly following a 3-day administration of ACTH. Protein kinase C prepared from the adrenal inner zones also bound zona glomerulosa detergent-treated nuclei but occupied fewer sites than the protein kinase C from the zona glomerulosa. In conclusion, the effects of chronic ACTH treatment on rat adrenal zona glomerulosa could be mediated by an increased level of protein kinase C in the nuclear fraction and possibly through its binding to specific 'acceptor sites'.
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PMID:The protein kinase C content is increased in the nuclear fraction of rat adrenal zona glomerulosa following long-term ACTH administration. 165 59


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