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PubMed1998

4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway.

Growth factors and hormones activate protein translation by phosphorylation and inactivation of the translational repressors, the eIF4E-binding proteins (4E-BPs), through a wortmannin- and rapamycin-sensitive signaling pathway. The mechanism by which signals emanating from extracellular signals lead to phosphorylation of 4E-BPs is not well understood. Here we demonstrate that the activity of the serine/threonine kinase Akt/PKB is required in a signaling cascade that leads to phosphorylation and inactivation of 4E-BP1. PI 3-kinase elicits the phosphorylation of 4E-BP1 in a wortmannin- and rapamycin-sensitive manner, whereas activated Akt-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. A dominant negative mutant of Akt blocks insulin-mediated phosphorylation of 4E-BP1, indicating that Akt is required for the in vivo phosphorylation of 4E-BP1. Importantly, an activated Akt induces phosphorylation of 4E-BP1 on the same sites that are phosphorylated upon serum stimulation. Similar to what has been observed with serum and growth factors, phosphorylation of 4E-BP1 by Akt inhibits the interaction between 4E-BP1 and eIF-4E. Furthermore, phosphorylation of 4E-BP1 by Akt requires the activity of FRAP/mTOR. FRAP/mTOR may lie downstream of Akt in this signaling cascade. These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1.

Adaptor Proteins, Signal Transducing↗

PubMed2007

The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity.

Hematopoietic stem cell (HSC) development is regulated by several signaling pathways and a number of key transcription factors, which include Scl/Tal1, Runx1, and members of the Smad family. However, it remains unclear how these various determinants interact. Using a genome-wide computational screen based on the well characterized Scl +19 HSC enhancer, we have identified a related Smad6 enhancer that also targets expression to blood and endothelial cells in transgenic mice. Smad6, Bmp4, and Runx1 transcripts are concentrated along the ventral aspect of the E10.5 dorsal aorta in the aorta-gonad-mesonephros region from which HSCs originate. Moreover, Smad6, an inhibitor of Bmp4 signaling, binds and inhibits Runx1 activity, whereas Smad1, a positive mediator of Bmp4 signaling, transactivates the Runx1 promoter. Taken together, our results integrate three key determinants of HSC development; the Scl transcriptional network, Runx1 activity, and the Bmp4/Smad signaling pathway.

Animals↗

PubMed2004

Inhibition of MAPK signaling pathways by VopA from Vibrio parahaemolyticus.

During infection, bacterial pathogens utilize a type III secretion system to inject effectors into the cytoplasm of a target cell where they disrupt the defense system of the host cell. Vibrio parahaemolyticus, a causative agent of gastroenteritis endemic in Southeast Asia, has a type III secretion system that encodes a novel member of the YopJ-like protein effector family, VopA (Vibrio outer protein A). Our studies revealed that Vibrio VopA encodes an evolutionarily conserved activity that is extremely potent and requires an intact catalytic site to abrogate signaling pathways in a manner distinct from that of other YopJ-like effectors. We observed that VopA efficiently inhibits the MAPK signaling pathways but not the NFkappaB pathway in mammalian cells. When expressed in yeast, VopA induces a growth arrest phenotype and also blocks yeast MAPK signaling pathways. Our observations provide insight into the immense diversity of targets utilized by YopJ-like effectors to manipulate eukaryotic signaling machineries that are important for the response and survival of the host cell during infection and/or symbiosis.

Amino Acid Sequence↗

PubMed2004

Tendon healing in vitro: activation of NIK, IKKalpha, IKKbeta, and NF- kappaB genes in signal pathway and proliferation of tenocytes.

Initiation of DNA transcription and proliferation of tendon cells are critical to tendon healing and require pivotal signals to the nucleus. Exploring intracellular signaling pathways pertinent to the healing process may reveal new approaches to accelerating the healing rate of the tendon. The authors investigated expression of NIK, IKKalpha, IKKbeta, and NF- kappaB genes in the signal pathway and tenocyte proliferation in an in vitro model in which cultured tenocytes were exposed to basic fibroblast growth factor (bFGF). Tenocytes were obtained from explant culture of rabbit intrasynovial tendons and were treated with bFGF at concentrations of 0, 2, or 10 ng/ml. Levels of expression of a series of genes for key factors along the signaling route--nuclear factor (NF)-kappaB-inducing kinase, inhibitor of kappa B kinase alpha and beta, and the NF-kappaB--were examined by quantitative analysis of products of reverse transcription and multiplex polymerase chain reactions. Proliferation of the cells was assessed with evaluation of growth curves and immunochemical labeling of the DNA of the cells. Expression levels of NIK, IKKalpha, IKKbeta, and NF-kappaB genes were significantly increased by bFGF at concentrations of 2 and 10 ng/ml. Western blot confirmed the increase of NF-kappaB in the tenocytes. The proliferation rate of the cells was significantly promoted by bFGF. Expression of these genes increased proportionately to the amounts of bFGF stimulating the cells and was correlated with increases in the proliferation rate. This study showed that expression of a series of genes along the NF-kappaB pathway was remarkably promoted by bFGF. The effects were proportionate to in vitro cell proliferation rate. Results of the study suggest that activation of a series of genes along the NF-kappaB pathway may play a pivotal role in initiating cell proliferation during the healing process of intrasynovial tendons. As activation of genes in signal transduction pathways is a new field in the biology of growth factor action with tremendous potential in promoting tissue repairs, manipulation of expression of a series of genes along the NF-kappaB pathway can be a new target of enhancing tendon healing through molecular mechanisms.

Animals↗

PubMed2006

Green tea extract and (-)-epigallocatechin-3-gallate inhibit mast cell-stimulated type I collagen expression in keloid fibroblasts via blocking PI-3K/AkT signaling pathways.

Keloid, a chronic fibro-proliferative disease, exhibits distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells (MCs), and a milieu of enriched cytokines. Previous studies have demonstrated that co-culture with MCs stimulate type I collagen synthesis in fibroblasts, but the signaling mechanisms remain largely unknown. In this study, we investigated the signaling pathways involved in MC-stimulated type I collagen synthesis and the effects of green tea extract (GTE) and its major catechin, (-)-epigallocatechin-3-gallate (EGCG), on collagen homeostasis in keloid fibroblasts. Our results showed that MCs significantly stimulated type I collagen expression in keloid fibroblasts, and the upregulation of type I collagen was significantly attenuated by blockade of phosphatidylinositol-3-kinase (PI-3K), mammalian target of rapamycin (mTOR), and p38 MAPK signaling pathways, but not by blockade of ERK1/2 pathway. Furthermore, GTE and EGCG dramatically inhibited type I collagen production possibly by interfering with the PI-3K/Akt/mTOR signaling pathway. Our findings suggest that interaction between MCs and keloid fibroblasts may contribute to excessive collagen accumulation in keloids and imply a therapeutic potential of green tea for the intervention and prevention of keloids and other fibrotic diseases.

Camellia sinensis↗

PubMed2004

A regulatory role of Wnt signaling pathway in the hematopoietic differentiation of murine embryonic stem cells.

One of the most important issues in stem cell research is to understand the regulatory mechanisms responsible for their differentiation. An extensive understanding of mechanism underlying the process of differentiation is crucial in order to prompt stem cells to perform a particular function after differentiation. To elucidate the molecular mechanisms responsible for the hematopoietic differentiation of embryonic stem cells (ESCs), we investigated murine ES cells for the presence of hematopoietic lineage markers as well as Wnt signaling pathway during treatments with different cytokines alone or in combination with another. Here we report that Wnt/beta-catenin signaling is down-regulated in hematopoietic differentiation of murine ES cells. We also found that differentiation induced by the interleukin-3, interleukin-6, and erythropoietin combinations resulted in high expression of CD3e, CD11b, CD45R/B220, Ly-6G, and TER-119 in differentiated ES cells. A high expression of beta-catenin was observed in two undifferentiated ES cell lines. Gene and protein expression analysis revealed that the members downstream of Wnt in this signaling pathway including beta-catenin, GSK-3beta, Axin, and TCF4 were significantly down-regulated as ES cells differentiated into hematopoietic progenitors. Our results show that the Wnt/beta-catenin signaling pathway plays a role in the hematopoietic differentiation of murine ESCs and also may support beta-catenin as a crucial factor in the maintenance of ES cells in their undifferentiated state.

Animals↗

PubMed1992

Differences between T helper cell type I (Th1) and Th2 cell lines in signalling pathways for induction of contact-dependent T cell help.

B cells get help in the antibody response by presenting antigen to helper T (Th) cells. Upon antigen recognition, T cells produce lymphokines that act as growth and differentiation factors for B cells, but resting B cells require additional helper signals that depend on cell contact with an activated Th cell. Like lymphokine secretion, contact help must be induced by antigen recognition or antigen receptor cross-linking in continuous Th cell lines. In the mouse, most CD4+ T cell lines can be classified into one of two stable differentiation states, Th1 or Th2, which produce different lymphokines and have different effector functions, activation requirements and cytoplasmic signalling mechanisms. This report demonstrates additional differences between Th1 and Th2 cell lines in the signalling pathways leading from the T cell antigen receptor to the induction of Th functions. In a system dependent on antigen presentation by B cells, B cell proliferation driven by Th2 cells but not Th1 cells was blocked by acute treatment with phorbol esters. Further experiments showed that phorbol esters blocked the induction of both contact help and lymphokine production in Th2 cells but not in Th1 cells. However, depletion of protein kinase C (PKC) activity by prolonged treatment of T cells with high concentrations of phorbol esters blocked induction of contact help and lymphokine production in Th1 cells but not in Th2 cells. These findings support the hypothesis that Th2 cells use a signalling pathway that is independent of PKC and that PKC activation can block this pathway. Since contact help and lymphokine secretion are affected in parallel, this difference between Th1 and Th2 cells probably reflects early events in the signalling pathway. Contact help and lymphokine production could be dissociated with cholera toxin and other cAMP agonists, but this dissociation could be explained by non-cAMP-related effects of cholera toxin on induction of contact help in Th2 cells, and by the direct effect of cAMP agonists on interleukin 2 gene transcription in Th1 cells reported by other laboratories.

Animals↗

PubMed1995

Nucleoprotein structure influences the response of the mouse mammary tumor virus promoter to activation of the cyclic AMP signalling pathway.

Recent studies have provided evidence of crosstalk between steroid receptors and cyclic AMP (cAMP) signalling pathways in the regulation of gene expression. A synergism between intracellular phosphorylation inducers and either glucocorticoids or progestins has been shown to occur during activation of the mouse mammary tumor virus (MMTV) promoter. We have investigated the effect of 8-Br-cAMP and okadaic acid, modulators of cellular kinases and phosphatases, on the hormone-induced activation of the MMTV promoter in two forms: a transiently transfected template with a disorganized, accessible nucleoprotein structure and a stably replicating template with an ordered, inaccessible nucleoprotein structure. Both okadaic acid and 8-Br-cAMP synergize significantly with either glucocorticoids or progestins in activating the transiently transfected MMTV template. In contrast, 8-Br-cAMP, but not okadaic acid, is antagonistic to hormone-induced activation of the stably replicating MMTV template. Nuclear run-on experiments demonstrate that this inhibition is a transcriptional effect on both hormone-induced transcription and basal transcription. Surprisingly, 8-Br-cAMP does not inhibit glucocorticoid-induced changes in restriction enzyme access and nuclear factor 1 binding. However, association of a complex with the TATA box region is inhibited in the presence of 8-Br-cAMP. Thus, cAMP treatment interferes with the initiation process but does not inhibit interaction of the receptor with the template. Since the replicated, ordered MMTV templates and the transfected, disorganized templates show opposite responses to 8-Br-cAMP treatment, we conclude that chromatin structure can influence the response of a promoter to activation of the cAMP signalling pathway.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1998

Phospholipase C cDNAs from sponge and hydra: antiquity of genes involved in the inositol phospholipid signaling pathway.

To know whether or not the set of genes involved in the inositol phospholipid signaling pathway already existed in the early evolution of animals, we carried out cloning of cDNAs encoding phospholipase Cs (PLCs) from Ephydatia fluviatilis (freshwater sponge) and Hydra magnipapillata strain 105 (hydra). We isolated two PLC cDNAs, PLC-betaS and PLC-gammaS, from sponge and three cDNAs, PLC-betaH1, PLC-betaH2, and PLC-deltaH, from hydra. From the domain organization and the divergence pattern in the PLC family tree, the sponge PLC-betaS and PLC-gammaS and the hydra PLC-deltaH are possibly homologous to the vertebrate PLC-beta, PLC-gamma and PLC-delta subtypes, respectively. A detailed phylogenetic analysis suggests that the hydra PLC-betaH1 and PLC-betaH2 are homologs of the vertebrate PLC-beta1/2/3/Drosophila PLC21 and the vertebrate PLC-beta4/Drosophila norpA, respectively. A phylogenetic analysis of the PLC family and the protein kinase C (PKC) family, together with that of the G protein alpha subunit (Galpha) family, revealed that the origin of the set of genes G(alpha)q, PLC, PKC involved in the inositol phospholipid signaling pathway is very old, going back to dates before the parazoan-eumetazoan split, the earliest branching among extant animal phyla.

Animals↗

PubMedDate not supplied

A truncated Ah receptor blocks the hypoxia and estrogen receptor signaling pathways: a viable approach for breast cancer treatment.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which requires heterodimerization with the Ah receptor nuclear translocator (Arnt) for function. Arnt is also a dimerization partner of the hypoxia inducible factor 1alpha (HIF-1alpha) for the hypoxia signaling. Additionally, Arnt is found to be a potent coactivator of the estrogen receptor (ER) signaling. Thus we examined whether the presence of an increased amount of AhR may suppress both the HIF-1alpha and ER signaling pathways by sequestering Arnt. We tested our hypothesis using a human AhR construct C Delta553 which is capable of heterodimerizing with Arnt in the absence of a ligand. Transient transfection studies using a corresponding luciferase reporter plasmid in MCF-7 cells showed that C Delta553 effectively suppressed the AhR, HIF-1alpha, and ER signaling pathways. Reverse transcription/real-time QPCR data showed that C Delta553 blocked the up-regulation of the target genes controlled by AhR (CYP1A1), HIF-1alpha (VEGF, aldolase C, and LDH-A), and ER (GREB1, pS2, and c-myc) in MCF-7 cells. Since both HIF-1alpha and ER are highly active in the ER-positive breast cancer, C Delta553 has the potential to be developed as a protein drug to treat breast cancer by blocking these two signaling pathways.

Adenocarcinoma↗

PubMed2003

Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs.

The ERK signaling pathway, also known as the p42/p44 MAP kinase pathway, is a major determinant in the control of cell growth, cell differentiation and cell survival. This pathway, which operates downstream of Ras, is often up-regulated in human tumors and as such represents an attractive target for anticancer therapy. In this chapter we review the rationale for targeting the components of the ERK pathway, either alone or in association with cytotoxic anticancer agents. We present the most advanced inhibitors of this pathway and discuss their specificity and mechanism of action.

Animals↗

PubMed2002

Lipoteichoic acid selectively induces the ERK signaling pathway in the cornea.

PURPOSE: To identify signal transduction pathways and gene expression induced by the bacterial cell wall component lipoteichoic acid (LTA) in human corneal keratocytes. METHODS: Human corneal keratocytes were cultured in the presence of 6.25 to 50 microg/ml LTA from Staphylococcus aureus. Induced DNA-binding of NF-kappaB was determined by electrophoretic mobility shift assays (EMSAs). Activation of MAP-kinase signaling pathways (p38, JNK-1/2, ERK-1/2, Elk 1, MEK-1/2, c-Raf) was evaluated by Western blotting using phospho-specific antibodies. To investigate the effect of LTA signaling on gene expression, keratocytes were transfected with a luciferase reporter gene under the control of serum response elements (SREs). LTA-induced gene expression was quantified using luciferase assays. RESULTS: Exposure of various concentrations of LTA up to 24 hours did not lead to activation of NF-kappaB, whereas TNF-alpha potently induced this transcription factor. A systematic analysis of LTA-activated MAPK pathways revealed no significant effects on JNK and p38, but a dose- and time-dependent phosphorylation of members of the ERK pathway. Analysis of the ERK-activating signaling cascade showed LTA-induced phosphorylation of ERK-1, MEK1/2, and c-Raf. ERK activity resulted in an enhanced transcription of an SRE-controlled reporter gene. CONCLUSIONS: LTA induces SRE-enhanced gene transcription in corneal keratocytes that is selectively mediated by the ERK pathway. Therefore, it seems possible that components of the bacterial cell wall such as LTA can alter the transcriptional program within the corneal stroma and thereby trigger an inflammatory response.

Adult↗

PubMed1999

The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors.

The rapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth program in response to nutrients such as nitrogen and carbon. The TOR1 and TOR2 kinases (TOR) control cytoplasmic protein synthesis and degradation through the conserved TAP42 protein. Upon phosphorylation by TOR, TAP42 binds and possibly inhibits type 2A and type-2A-related phosphatases; however, the mechanism by which TOR controls nuclear events such as global repression of starvation-specific transcription is unknown. Here we show that TOR prevents transcription of genes expressed upon nitrogen limitation by promoting the association of the GATA transcription factor GLN3 with the cytoplasmic protein URE2. The binding of GLN3 to URE2 requires TOR-dependent phosphorylation of GLN3. Phosphorylation and cytoplasmic retention of GLN3 are also dependent on the TOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4. TOR inhibits expression of carbon-source-regulated genes by stimulating the binding of the transcriptional activators MSN2 and MSN4 to the cytoplasmic 14-3-3 protein BMH2. Thus, the TOR signalling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm.

14-3-3 Proteins↗

PubMed2006

Targeting the ERK signaling pathway in cancer therapy.

The extracellular signal-regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes such as proliferation, survival, differentiation and motility. This pathway is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. Because of its multiple roles in the acquisition of a complex malignant phenotype, specific blockade of the ERK pathway is expected to result in not only an anti-proliferative effect but also in anti-metastatic and anti-angiogenic effects in tumor cells. Recently potent small-molecule inhibitors targeting the components of the ERK pathway have been developed. Among them, BAY 43-9006 (Raf inhibitor), and PD184352, PD0325901 and ARRY-142886 (MEK1/2 inhibitors) have reached the clinical trial stage. We briefly discuss the possibility that combination of ERK pathway inhibitors (cytostatic agents) and conventional anticancer drugs (cytotoxic agents) provides an excellent basis for the development of new chemotherapeutic strategies against cancer.

Antineoplastic Agents↗

PubMed1998

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3' kinase were highly apoptotic, suggesting that recruitment of PI-3' kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3' kinase binding site was noted in tumors derived from the strains expressing the PI-3' kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3' kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3' kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.

Adaptor Proteins, Signal Transducing↗

PubMed2003

The evolution of signalling pathways in animal development.

Despite the bewildering number of cell types and patterns found in the animal kingdom, only a few signalling pathways are required to generate them. Most cell-cell interactions during embryonic development involve the Hedgehog, Wnt, transforming growth factor-beta, receptor tyrosine kinase, Notch, JAK/STAT and nuclear hormone pathways. Looking at how these pathways evolved might provide insights into how a few signalling pathways can generate so much cellular and morphological diversity during the development of individual organisms and the evolution of animal body plans.

Animals↗

PubMed2000

gp130-Dependent signalling pathway is not enhanced in gp130 transgenic heart after LIF stimulation.

Activation of gp130 transduces a hypertrophic signal in the heart, but it is not clear whether signalling through gp130 is enhanced when gp130 is overexpressed in vivo. We generated gp130 transgenic mice (TG) and examined the activation of signalling pathways downstream of gp130 in the hearts. The tyrosine phosphorylation of gp130 was enhanced, the phosphorylation of STAT3 and ERK (extracellular signal regulated kinase) 1/2 was increased and induction of the beta-myosin heavy chain (MHC) gene was observed in TG hearts without significant phenotypic changes. Intravenous administration of leukaemia inhibitory factor (LIF) induced tyrosine phosphorylation of STAT3 and ERK 1/2 and expression of c-fos and beta-MHC mRNAs in wild-type littermates' (WT) hearts. However, enhancement of STAT3 and ERK 1/2 phosphorylation or augmented mRNA expressions was not observed in TG hearts after LIF stimulation. Next, STAT-induced STAT inhibitor (SSI) mRNA expression was examined. The expression of SSI-1, SSI-2, and SSI-3 mRNAs was significantly augmented in TG hearts after LIF stimulation. These results indicate that overexpressed gp130 does not always enhance downstream signals in the hearts and suggest that the SSI family plays a role in the regulation of the gp130-dependent signalling pathway in the hearts.

Age Factors↗

PubMed2005

Involvement of cAMP/cAMP-dependent protein kinase signaling pathway in regulation of Na+,K+-ATPase upon activation of opioid receptors by morphine.

The depolarization of neurons induced by impairment of Na+,K+-ATPase activity after long-term opiate treatment has been shown to involve the development of opioid dependence. However, the mechanisms underlying changes in Na+,K+-ATPase activity after opioid treatment are unclear. The best-established molecular adaptation to long-term opioid exposure is up-regulation of the cAMP/cAMP-dependent protein kinase (PKA) signaling pathway; this study, therefore, was undertaken to investigate the role of up-regulation of cAMP/PKA signaling pathway in alteration of the mouse hippocampal Na+,K+-ATPase activity. The results demonstrated that short-term morphine treatment dose dependently stimulated Na+,K+-ATPase activity. This action could be significantly suppressed by adenylyl cyclase activator 7beta-acetoxy-8,13-epoxy-1alpha,6beta,9alpha-trihydroxylabd-14-en-11-one (forskolin), or the cAMP analog dibutyryl-cAMP. Contrary to short-term morphine treatment, long-term treatment significantly inhibited Na+,K+-ATPase activity. Moreover, an additional decrease in Na+,K+-ATPase activity was observed by naloxone precipitation. The effects of both short- and long-term morphine treatment on Na+,K+-ATPase activity were naltrexone-reversible. The regulation of Na+,K+-ATPase activity by morphine was inversely correlated with intracellular cAMP accumulation. N-[2-(4-Bromocinnamylamino)ethyl]-5-isoquinoline (H89), a specific PKA inhibitor, mimicked the stimulatory effect of short-term morphine but antagonized the inhibitory effect of long-term morphine treatment on Na+,K+-ATPase activity. However, okadaic acid, a protein phosphatase inhibitor, suppressed short-term morphine stimulation but potentiated long-term morphine inhibition of Na+,K+-ATPase activity. The regulation of Na+,K+-ATPase activity by morphine treatment seemed to associate with the alteration in phosphorylation level but not to be relevant to the change in abundance of Na+,K+-ATPase. These findings strongly demonstrate that cAMP/PKA signaling pathway involves regulation of Na+,K+-ATPase activity after activation of opioid receptors.

Adenylyl Cyclases↗