scholarly journals Cellular Effects of Rhynchophylline and Relevance to Sleep Regulation

2021 ◽  
Vol 3 (2) ◽  
pp. 312-341
Author(s):  
Maria Neus Ballester Roig ◽  
Tanya Leduc ◽  
Cassandra C. Areal ◽  
Valérie Mongrain
Keyword(s):  
Sleep Time ◽  
Sleep Regulation ◽  
Neuronal Communication ◽  
Cellular Effects ◽  
Pathological Conditions ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Cellular Pathways ◽  
Phosphoinositide 3 Kinase ◽  
Protein Kinase Akt

Uncaria rhynchophylla is a plant highly used in the traditional Chinese and Japanese medicines. It has numerous health benefits, which are often attributed to its alkaloid components. Recent studies in humans show that drugs containing Uncaria ameliorate sleep quality and increase sleep time, both in physiological and pathological conditions. Rhynchophylline (Rhy) is one of the principal alkaloids in Uncaria species. Although treatment with Rhy alone has not been tested in humans, observations in rodents show that Rhy increases sleep time. However, the mechanisms by which Rhy could modulate sleep have not been comprehensively described. In this review, we are highlighting cellular pathways that are shown to be targeted by Rhy and which are also known for their implications in the regulation of wakefulness and sleep. We conclude that Rhy can impact sleep through mechanisms involving ion channels, N-methyl-d-aspartate (NMDA) receptors, tyrosine kinase receptors, extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/RAC serine/threonine-protein kinase (AKT), and nuclear factor-kappa B (NF-κB) pathways. In modulating multiple cellular responses, Rhy impacts neuronal communication in a way that could have substantial effects on sleep phenotypes. Thus, understanding the mechanisms of action of Rhy will have implications for sleep pharmacology.

scholarly journals Insulin stimulation of pyruvate dehydrogenase in adipocytes involves two distinct signalling pathways

2003 ◽  
Vol 369 (2) ◽  
pp. 351-356 ◽  
Author(s):  
Sam A. JOHNSON ◽  
Richard M. DENTON
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Maximal Effect ◽  
Insulin Stimulation ◽  
Rat Adipocytes ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Stimulation Of

In isolated rat adipocytes, the insulin stimulation of pyruvate dehydrogenase can be partially inhibited by inhibitors of PI3K (phosphoinositide 3-kinase) and MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase). In combination, U0126 and wortmannin completely block the insulin stimulation of pyruvate dehydrogenase. It is concluded that the effect of insulin on pyruvate dehydrogenase in rat adipocytes involves two distinct signalling pathways: one is sensitive to wortmannin and the other to U0126. The synthetic phosphoinositolglycan PIG41 can activate pyruvate dehydrogenase but the activation is only approx. 30% of the maximal effect of insulin. This modest activation can be completely blocked by wortmannin alone, suggesting that PIG41 acts through only one of the pathways leading to the activation of pyruvate dehydrogenase.

Insulin inhibits glucocorticoid-stimulated L-type 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression by activation of the c-Jun N-terminal kinase pathway

2001 ◽  
Vol 353 (2) ◽  
pp. 267-273 ◽  
Author(s):  
Elisabet DE LOS PINOS ◽  
Silvia FERNÁNDEZ DE MATTOS ◽  
Manel JOAQUIN ◽  
Albert TAULER
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Glucocorticoid Receptor ◽  
Map Kinase ◽  
Inhibitory Effect ◽  
Interacting Protein ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Ribosomal S6 Kinase ◽  
Phosphoinositide 3 Kinase

The hepatic isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PF2K/Fru-2,6-BPase) is transcriptionally stimulated by glucocorticoids, whereas insulin blocks this stimulatory effect. Although this inhibitory effect has been extensively reported, nothing is known about the signalling pathway responsible. We have used well-characterized inhibitors for proteins involved in different signalling cascades to assess the involvement of these pathways on the transcriptional regulation of glucocorticoid-stimulated PF2K/Fru-2,6-BPase by insulin. Our results demonstrate that the phosphoinositide 3-kinase, p70/p85 ribosomal S6 kinase, extracellular signal-regulated protein kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase pathways are not involved in the inhibitory effect of insulin on glucocorticoid-stimulated PF2K/Fru-2,6-BPase. To evaluate the implication of the MAP kinase/ERK kinase (MEK)-4Őstress-activated protein kinaseŐc-Jun-N-terminal protein kinase (‘JNKŐSAPK’) pathway we overexpressed the N-terminal JNK-binding domain of the JNK-interacting protein 1 (‘JIP-1’), demonstrating that activation of JNK is necessary for the insulin inhibitory effect. Moreover, overexpression of MEK kinase 1 and JNKŐhaemagglutinin resulted in the inhibition of the glucocorticoid-stimulated PF2K/Fru-2,6-BPase. These results provide clear and specific evidence for the role of JNK in the insulin inhibition of glucocorticoid-stimulated PF2K/Fru-2,6-BPase gene expression. In addition, we performed experiments with a mutant of the glucocorticoid receptor in which the JNK phosphorylation target Ser-246 had been mutated to Ala. Our results demonstrate that the phosphorylation of the glucocorticoid receptor on Ser-246 is not responsible for the JNK repression of glucocorticoid-stimulated PF2K/Fru-2,6-BPase gene expression.

scholarly journals Gαq binds to p110α/p85α phosphoinositide 3-kinase and displaces Ras

2006 ◽  
Vol 394 (3) ◽  
pp. 557-562 ◽  
Author(s):  
Lisa M. Ballou ◽  
Mohar Chattopadhyay ◽  
Yan Li ◽  
Suzanne Scarlata ◽  
Richard Z. Lin
Keyword(s):  
Fluorescence Spectroscopy ◽  
Cell Types ◽  
Binding Domain ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Ras Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Co Precipitation

Several studies have reported that activation of Gq-coupled receptors inhibits PI3K (phosphoinositide 3-kinase) signalling. In the present study, we used purified proteins to demonstrate that Gαq directly inhibits p110α/p85α PI3K in a GTP-dependent manner. Activated Gαq binds to the p110α/p85α PI3K with an apparent affinity that is seven times stronger than that for Gαq·GDP as measured by fluorescence spectroscopy. In contrast, Gαq did not bind to the p110γ PI3K. Fluorescence spectroscopy experiments also showed that Gαq competes with Ras, a PI3K activator, for binding to p110α/p85α. Interestingly, co-precipitation studies using deletion mutants showed that Gαq binds to the p85-binding domain of p110α and not to the Ras-binding domain. Expression of constitutively active GαqQ209L in cells inhibited Ras activation of the PI3K/Akt pathway but had no effect on Ras/Raf/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] signalling. These results suggest that activation of Gq-coupled receptors leads to increased binding of Gαq·GTP to some isoforms of PI3K, which might explain why these receptors inhibit this signalling pathway in certain cell types.

scholarly journals Protein kinase C (PKC)-δ/-ε mediate the PKC/Akt-dependent phosphorylation of extracellular signal-regulated kinases 1 and 2 in MCF-7 cells stimulated by bradykinin

2006 ◽  
Vol 188 (1) ◽  
pp. 79-89 ◽  
Author(s):  
S Greco ◽  
C Storelli ◽  
S Marsigliante
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Breast Cancer Cells ◽  
Mitogen Activated Protein Kinase ◽  
Kinase C ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Mcf 7 ◽  
Protein Kinase Kinase

In this paper the signal transduction pathways evoked by bradykinin (BK) in MCF-7 breast cancer cells were investigated. BK activation of the B2 receptor provoked: (a) the phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2); (b) the translocation from the cytosol to the membrane of the conventional protein kinase C-α (PKC-α) and novel PKC-δ and PKC-ε; (c) the phosphorylation of protein kinase B (PKB/ Akt); (d) the proliferation of MCF-7 cells. The BK-induced ERK1/2 phosphorylation was completely blocked by PD98059 (an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK)) and by LY294002 (an inhibitor of phosphoinositide 3-kinase (PI3K)), and was reduced by GF109203X (an inhibitor of both novel and conventional PKCs); Gö6976, a conventional PKCs inhibitor, did not have any effect. The BK-induced phosphorylation of PKB/Akt was blocked by LY294002 but not by PD98059. Furthermore, LY294002 inhibited the BK-provoked translocation of PKC-δ and PKC-ε suggesting that PI3K may be upstream to PKCs. Finally, the proliferative effects of BK were blocked by PD98059, GF109203X and LY294002. These observations demonstrate that BK acts as a proliferative agent in MCF-7 cells activating intracellular pathways involving novel PKC-δ/-ε, PKB/Akt and ERK1/2.

Regulation of IL-6-type cytokine responses by MAPKs

2014 ◽  
Vol 42 (1) ◽  
pp. 59-62 ◽  
Author(s):  
Ana P. Costa-Pereira
Keyword(s):  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Cell Type ◽  
Fully Integrated ◽  
Extracellular Signal Regulated Kinase ◽  
Cellular Environment ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
The Stability

IL-6 (interleukin 6)-type cytokines are pleiotropic molecules, critical for cellular homoeostasis and with well-recognized roles in several human diseases. They all activate JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling and, depending on the particular cytokine, cell type and cellular environment, they can also trigger the activation of MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) cascades. Although it is clear that JAK/STAT and MAPK reciprocally regulate each other, how these signalling pathways are fully integrated remains to be fully understood. Not only do cells have to be able to integrate and conciliate what are often contradictory signalling cues, but they are also subject to complex regulatory mechanisms involving these pathways. More specifically, we have shown recently that ERK2 (extracellular-signal-regulated kinase 2) is required for the transcriptional regulation of gp130 (glycoprotein 130), a key receptor complex component for most IL-6-type cytokines. ERK2 not only binds to the gp130 promoter and is required for full expression of the protein, but it also regulates the stability of gp130 mRNA. This function of ERK2 is not shared by ERK1 and it probably represents an entirely novel function for this prominent kinase.

scholarly journals Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-xiang Wang ◽  
Xu Zhang ◽  
Qing-yang Ma ◽  
Lan-dian Hu ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Selective Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Adaptive Resistance ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Genomic Adaptation ◽  
Phosphoinositide 3 Kinase ◽  
Specific Inhibitors

AbstractPhosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.

scholarly journals Role of phosphoinositide 3-kinase and the Cbl adaptor protein in coupling the α4β1 integrin to mitogen-activated protein kinase signalling

2000 ◽  
Vol 345 (2) ◽  
pp. 385-392 ◽  
Author(s):  
Lisa D. FINKELSTEIN ◽  
Yoji SHIMIZU
Keyword(s):  
Protein Kinase ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Hl60 Cells ◽  
Intracellular Signals ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Stimulation Of

Cell adhesion mediated by β1 integrin receptors leads to the initiation of intracellular signals that affect cell differentiation and survival. Here we have analysed the mechanism by which the α4β1 integrin activates the mitogen-activated protein kinase pathway in HL60 cells, a myelomonocytic cell line that lacks the expression of focal adhesion kinase. A role for phosphoinositide 3-kinase (PI-3K) in α4 integrin-mediated activation of extracellular signal-regulated protein kinase 2 (ERK2) is suggested by the ability of PI-3K inhibitors and a dominant-negative form of the p85 subunit of PI-3K to block the activation of ERK2 by integrin. Stimulation of α4β1 integrins on HL60 cells also leads to increased tyrosine phosphorylation of the 120 kDa adaptor protein Cbl. PI-3K activity associated with Cbl also increases on the stimulation of α4β1 integrins, although immunodepletion experiments suggest that Cbl-associated PI-3K does not account for all of the PI-3K activity induced on the stimulation of integrins in these cells. The expression of wild-type Cbl or the 70Z/3 Cbl mutant enhances basal ERK2 activity in transfectants with a minimal effect on α4 integrin-mediated ERK2 activity. In contrast, overexpression of the Hut Cbl truncation mutant, which does not associate with p85, has no effect on the ERK2 pathway. These results suggest that PI-3K has a major role in coupling α4β1 integrins to ERK2 activation in myeloid cells and that the Cbl adaptor protein has a role in basal, but not α4β1 integrin-mediated, activation of ERK2.

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