Selective desensitization of protein-kinase-C-mediated platelet granule secretion with prolonged incubation of protein kinase C activators despite sustained 45 kDa phosphorylation

1988 ◽  
Vol 16 (5) ◽  
pp. 804-806
Author(s):  
SUSHILA KRISHNAMURTHI ◽  
YATIN PATEL ◽  
SUNIL JOSEPH ◽  
VIJAY V. KAKKAR
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Prolonged Incubation ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Granule Secretion

scholarly journals Collagen-induced platelet activation mainly involves the protein kinase C pathway

1990 ◽  
Vol 268 (2) ◽  
pp. 325-331 ◽  
Author(s):  
A Karniguian ◽  
F Grelac ◽  
S Levy-Toledano ◽  
Y J Legrand ◽  
F Rendu
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Platelet Activation ◽  
Membrane Receptors ◽  
Lag Phase ◽  
Response Curves ◽  
Kinase C ◽  
Metabolic Event ◽  
Granule Secretion

This study analyses early biochemical events in collagen-induced platelet activation. An early metabolic event occurring during the lag phase was the activation of PtdIns(4,5)P2-specific phospholipase C. Phosphatidic acid (PtdOH) formation, phosphorylation of P43 and P20, thromboxane B2 (TXB2) synthesis and platelet secretion began after the lag phase, and were similarly time-dependent, except for TXB2 synthesis, which was delayed. Collagen induced extensive P43 phosphorylation, whereas P20 phosphorylation was weak and always lower than with thrombin. The dose-response curves of P43 phosphorylation and granule secretion were similar, and both reached a peak at 7.5 micrograms of collagen/ml, a dose which induced half-maximal PtdOH and TXB2 formation. Sphingosine, assumed to inhibit protein kinase C, inhibited P43 phosphorylation and secretion in parallel. However, sphingosine was not specific for protein kinase C, since a 15 microM concentration, which did not inhibit P43 phosphorylation, blocked TXB2 synthesis by 50%. Sphingosine did not affect PtdOH formation at all, even at 100 microM, suggesting that collagen itself induced this PtdOH formation, independently of TXB2 generation. The absence of external Ca2+ allowed the cleavage of polyphosphoinositides and the accumulation of InsP3 to occur, but impaired P43 phosphorylation, PtdOH and TXB2 formation, and secretion; these were only restored by adding 0.11 microM-Ca2+. In conclusion, stimulation of platelet membrane receptors for collagen initiates a PtdInsP2-specific phospholipase C activation, which is independent of external Ca2+, and might be the immediate receptor-linked response. A Ca2+ influx is indispensable to the triggering of subsequent platelet responses. This stimulation predominantly involves the protein kinase C pathway associated with secretion, and appears not to be mediated by TXB2, at least during its initial stage.

Activators of protein kinase A and of protein kinase C inhibit MDCK cell myo-inositol and betaine uptake.

1995 ◽  
Vol 6 (6) ◽  
pp. 1559-1564
Author(s):  
A S Preston ◽  
A Yamauchi ◽  
H M Kwon ◽  
J S Handler
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Translational Regulation ◽  
Mdck Cells ◽  
Relative Effect ◽  
Amino Acid Sequences ◽  
Prolonged Incubation ◽  
Kinase C ◽  
Kinase A

Amino acid sequences of the myo-inositol and betaine cotransporters that are induced in MDCK cells by hypertonicity include consensus sequences for phosphorylation by protein kinase A and by protein kinase C. To test for the effect of activation of protein kinases A and C on the activity of those cotransporters, MDCK cells were exposed to activators of each kinase and the activity of both cotransporters was assayed. Incubation with 8-bromoadenosine 3':5'-cyclic monophosphate (8Br-cAMP) or 3-isobutyl-1-methylxanthine (IBMX), activators of protein kinase A, and incubation with an active phorbol ester or with an active diacylglycerol, activators of protein kinase C, inhibited the activity of both cotransporters by about 30%. The relative effect of the activation of protein kinase A and of protein kinase C was similar in hypertonic and isotonic cells. The effects of activators of protein kinase A and of protein kinase C were not additive. The two cotransporters behaved differently when protein kinase C activity was down-regulated by prolonged incubation with a higher concentration of phorbol 12-myristate 13-acetate. There was a doubling of activity of the myo-inositol cotransporter and no change in the activity of the betaine cotransporter in hypertonic and isotonic cells. Although the mechanisms of the effects of activation of the two kinases remain to be established, it is clear that the kinases can mediate post-translational regulation of the uptake of compatible osmolytes.

Protein Kinase C Activators as Synaptogenic and Memory Therapeutics

2009 ◽  
Vol 342 (12) ◽  
pp. 689-698 ◽  
Author(s):  
Miao-Kun Sun ◽  
Daniel L. Alkon
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase C ◽  
Protein Kinase C Activators

scholarly journals Calcium mobilization and protein kinase C activation are required for cholecystokinin stimulation of pancreatic cholesterol esterase secretion

1995 ◽  
Vol 306 (2) ◽  
pp. 605-608 ◽  
Author(s):  
J Brodt-Eppley ◽  
D Y Hui
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Digestive Enzyme ◽  
Calcium Mobilization ◽  
Cholesterol Esterase ◽  
Ionophore A23187 ◽  
Prolonged Incubation ◽  
Ar42j Cells ◽  
Kinase C ◽  
Stimulation Of

The bile salt-stimulated cholesterol esterase is a digestive enzyme synthesized by the acinar cells of the pancreas. Previous results have shown that cholesterol esterase biosynthesis and secretion in the AR42J pancreatoma cells could be increased 3-5-fold by intestinal hormones such as cholecystokinin (CCK). The purpose of the current study is to explore the signalling mechanism by which CCK stimulation of AR42J cells results in increased biosynthesis and secretion of the cholesterol esterase. The results showed that the CCK-induced cholesterol esterase secretion could be mimicked by addition of the Ca2+ ionophore A23187 or by transient incubation of AR42J cells with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA). Cholesterol esterase stimulation by CCK, A23187 and PMA could be abolished by the calcium chelator BAPTA or by specific protein kinase C inhibitors such as chelerythrine. Additionally, prolonged incubation of AR42J cells with PMA to reduce the protein kinase C level, also reduced CCK-stimulated cholesterol esterase secretion to a level similar to that observed in control cells. Taken together, these data suggested that CCK activation of cholesterol esterase secretion may be mediated by a Ca(2+)-dependent protein kinase C pathway, requiring increases in calcium mobilization and activation of protein kinase C.

scholarly journals Induction of heparin-binding epidermal growth factor-like growth factor mRNA by protein kinase C activators

1994 ◽  
Vol 46 (3) ◽  
pp. 690-695 ◽  
Author(s):  
Mian-Shin Tan ◽  
Jer-Chia Tsai ◽  
Yau-Jiunn Lee ◽  
Hung-Chun Chen ◽  
Shyi-Jang Shin ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Heparin Binding ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Epidermal Growth

scholarly journals Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors that Potently Reactivate Latent HIV

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 609
Author(s):  
Francesca Curreli ◽  
Shahad Ahmed ◽  
Sofia M. Benedict Victor ◽  
Asim K. Debnath
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Synergistic Effect ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Latent Virus ◽  
Hiv Latency ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Latent Hiv

Combination antiretroviral therapy (cART) is successful in maintaining undetectable levels of HIV in the blood; however, the persistence of latent HIV reservoirs has become the major barrier for a HIV cure. Substantial efforts are underway in finding the best latency-reversing agents (LRAs) to purge the latent viruses from the reservoirs. We hypothesize that identifying the right combination of LRAs will be the key to accomplishing that goal. In this study, we evaluated the effect of combinations of three protein kinase C activators (prostratin, (-)-indolactam V, and TPPB) with four histone deacetylase inhibitors (AR-42, PCI-24781, givinostat, and belinostat) on reversing HIV latency in different cell lines including in a primary CD4+ T-cell model. Combinations including indolactam and TPPB with AR-42 and PCI produced a strong synergistic effect in reactivating latent virus as indicated by higher p24 production and envelope gp120 expression. Furthermore, treatment with TPPB and indolactam greatly downregulated the cellular receptor CD4. Indolactam/AR-42 combination emerged from this study as the best combination that showed a strong synergistic effect in reactivating latent virus. Although AR-42 alone did not downregulate CD4 expression, indolactam/AR-42 showed the most efficient downregulation. Our results suggest that indolactam/AR-42 is the most effective combination, showing a strong synergistic effect in reversing HIV latency combined with the most efficient CD4 downregulation.

DIACYLGLYCEROL AND PHORBOL ESTER REDUCE AEQUORIN-INDICATED [Ca++] ELEVATIONS INDUCED BY THROMBIN OR ADP

1987 ◽  
Author(s):  
J A Ware ◽  
M Smith ◽  
E W Salzman
Keyword(s):  
Protein Kinase C ◽  
Platelet Aggregation ◽  
Protein Kinase ◽  
Phorbol Ester ◽  
Time Dependent ◽  
Dependent Manner ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Protein Kinase C Inhibitor ◽  
Ca Homeostasis

Platelet aggregation and secretion induced by phorbol ester (PMA) or diacylglycerol (DAG) are preceded by an increase in [Ca++] that is detected byaequorin, but not by quin2, fura-2, or indo-1, suggesting that these indicatorsreflect different aspects of Ca++ homeostasis, possibly different functional Ca++ pools. Addition of two conventional agonists in subthreold concentrations synergistically enhances the [Ca++] rise and aggregation.However, if PMA or DAG is the first agonist the subsequent quin2-indicated [Ca++] rise after thrombin is reduced.Whether aequorin-indicated [Ca++] is similarly affected is unknown. We studied gel-filtered platelets loaded with aequorin or a fluorophore and added PMA, DAG, thrombin or ADP, alone or in combination. Either PMA or DAG alone caused a concentration-dependent increase in [Ca++] detectable with aequorin but not with the fluorophores; simultaneous addition of thrombin or ADP with DAG or PMA produced a larger [Ca++] rise than either alone. However, addition of DAG or PMA as a first agonist reduced subsequent aequorin-indicated [Ca++] rises following thrombin or ADP in a concentration and time-dependent manner. Inhibition of ADP or thrombin-induced [Ca++] rise was not always accompanied by inhibition of aggregation or secretion. Combination of subthreshold concentrations of ADP and thrombin produced an enhanced [Ca++] rise and aggregation. However, this synergistic effect was inhibited by preincubation with DAG or PMA. Neither this effect nor DAG-induced [Ca++] rise was inhibited by the protein kinase C inhibitor H-7. In genera^ preincubation of platelets with an agonist enhances Ca rise and aggregation in response to a second agonist; in contrasl protein kinase C activators, which themselves elevate [Ca++] as shown by aequorin, inhibit aequorin-indicated Ca rises after ADP or thrombin, and limit synergism between these two agonists.

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