Distribution by Scientific Domains
Distribution within Life Sciences

Kinds of Kinase

  • AMP-activat protein kinase
  • RNA-activat protein kinase
  • Rho-associat kinase
  • activated kinase
  • activating kinase
  • adenosine kinase
  • adenylate kinase
  • adhesion kinase
  • amp-activated protein kinase
  • amp-dependent protein kinase
  • anaplastic lymphoma kinase
  • arginine kinase
  • aurora kinase
  • b kinase
  • bruton tyrosine kinase
  • c-jun-n-terminal kinase
  • ca2+/calmodulin-dependent protein kinase
  • calcium-dependent protein kinase
  • camp-dependent protein kinase
  • camp-protein kinase
  • casein kinase
  • cgmp-dependent protein kinase
  • chain kinase
  • checkpoint kinase
  • creatine kinase
  • cyclin dependent kinase
  • cyclin-dependent kinase
  • death-associated protein kinase
  • dehydrogenase kinase
  • deoxycytidine kinase
  • dependent kinase
  • dependent protein kinase
  • diacylglycerol kinase
  • diphosphate kinase
  • downstream kinase
  • egfr tyrosine kinase
  • epidermal growth factor receptor tyrosine kinase
  • erk map kinase
  • extracellular regulated kinase
  • extracellular signal-regulated kinase
  • extracellular signal-regulated protein kinase
  • extracellular signal-related kinase
  • extracellular-regulated kinase
  • extracellular-regulated protein kinase
  • factor receptor tyrosine kinase
  • family kinase
  • fms-like tyrosine kinase
  • focal adhesion kinase
  • glycerol kinase
  • glycogen synthase kinase
  • growth factor receptor tyrosine kinase
  • guanylate kinase
  • herpes simplex virus thymidine kinase
  • histidine kinase
  • histidine protein kinase
  • integrin-linked kinase
  • janus kinase
  • jun kinase
  • jun n-terminal kinase
  • jun n-terminal protein kinase
  • kinase kinase
  • leucine-rich repeat kinase
  • light chain kinase
  • lymphoma kinase
  • lyn kinase
  • map kinase
  • map kinase kinase
  • mapk kinase
  • mapk/erk kinase
  • membrane-associated guanylate kinase
  • mitogen-activated protein kinase
  • mitogen-activated protein kinase kinase
  • monophosphate kinase
  • myosin light chain kinase
  • n-terminal kinase
  • n-terminal protein kinase
  • non-receptor tyrosine kinase
  • nucleoside diphosphate kinase
  • pantothenate kinase
  • phosphoglycerate kinase
  • pi-3 kinase
  • pi3 kinase
  • polo-like kinase
  • protein extracellular signal-regulated kinase
  • protein kinase
  • protein kinase kinase
  • protein s6 kinase
  • protein tyrosine kinase
  • pyruvate dehydrogenase kinase
  • pyruvate kinase
  • receptor kinase
  • receptor tyrosine kinase
  • receptor-like kinase
  • regulated kinase
  • relate kinase
  • repeat kinase
  • rho kinase
  • ribosomal protein s6 kinase
  • ribosomal s6 kinase
  • rna-dependent protein kinase
  • s6 kinase
  • sensor histidine kinase
  • sensor kinase
  • ser/thr kinase
  • serine kinase
  • serine-threonine kinase
  • serum creatine kinase
  • several kinase
  • several protein kinase
  • shikimate kinase
  • signal-regulated kinase
  • signal-regulated protein kinase
  • signal-related kinase
  • simplex virus thymidine kinase
  • specific kinase
  • sphingosine kinase
  • src family kinase
  • src kinase
  • src tyrosine kinase
  • src-family kinase
  • src-family tyrosine kinase
  • stress-activated protein kinase
  • synthase kinase
  • terminal kinase
  • threonine kinase
  • threonine protein kinase
  • thymidine kinase
  • thymidylate kinase
  • upstream kinase
  • virus thymidine kinase
  • vitro kinase

  • Terms modified by Kinase

  • kinase activation
  • kinase activator
  • kinase activity
  • kinase anchoring protein
  • kinase b
  • kinase c
  • kinase c activation
  • kinase c activator
  • kinase c activity
  • kinase c inhibition
  • kinase c inhibitor
  • kinase c isoform
  • kinase c isozyme
  • kinase c pathway
  • kinase c substrate
  • kinase c.
  • kinase cascade
  • kinase deficiency
  • kinase domain
  • kinase erk1/2
  • kinase family
  • kinase function
  • kinase g
  • kinase gene
  • kinase i
  • kinase ii
  • kinase inhibition
  • kinase inhibitor
  • kinase inhibitor therapy
  • kinase iv
  • kinase kinase
  • kinase level
  • kinase mrna
  • kinase mutant
  • kinase mutation
  • kinase pathway
  • kinase phosphorylation
  • kinase protein
  • kinase reaction
  • kinase receptor
  • kinase signal
  • kinase signaling
  • kinase signaling pathway
  • kinase signalling
  • kinase signalling pathway
  • kinase src
  • kinase substrate
  • kinase system
  • kinase target

  • Selected Abstracts


    Ping-Ying Lee
    SUMMARY 1We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-,B and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. 2Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 µmol/L), LPS + tetrodotoxin (TTX; 1 µmol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 µmol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. 3We found that LPS significantly increased the concentrations of TLR-4, NF-,B and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-,B, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. 4These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-,B and MAPKs in activated macrophages. Moreover, these effects involve VSSC. [source]

    Characterization of p70 S6 kinase 1 in early development of mouse embryos

    Xiao-Yan Xu
    Abstract The mTOR kinase controls cell growth, proliferation, and survival through two distinct multiprotein complexes mTORC1 and mTORC2. p70 S6 Kinase 1 (S6K1) is characterized as downstream effector of mTOR. Until recently, the connection between S6K1 and mTORC1 /mTORC2 during the early development of mouse embryos has not been well elucidated. Here, the expression level of total S6K1 and its phosphorylation at Thr389 was determined in four phases of one-cell embryos. S6K1 was active throughout the cell cycle especially with higher activity in G2 and M phases. Rapamycin decreased the activity of M-phase promoting factor (MPF) and delayed the first mitotic cleavage. Down-regulating mTOR and raptor reduced S6K1 phosphorylation at Thr389 in one-cell embryos. Furthermore, rapamycin and microinjection of raptor shRNA decreased the immunofluorescent staining of Thr389 phospho-S6K1. It is proposed that mTORC1 may be involved in the control of MPF by regulating S6K1 during the early development of mouse embryos. Developmental Dynamics 238:3025,3034, 2009. © 2009 Wiley-Liss, Inc. [source]

    Different effects of pioglitazone and rosiglitazone on lipid metabolism in mouse cultured liver explants

    Louiza Djaouti
    Abstract Background Pioglitazone (PIO) and rosiglitazone (ROSI) are widely used as oral antidiabetic agents for treatment of type 2 diabetes. Although these medications exert similar effects on blood glucose, recent clinical studies indicated that PIO has a more pronounced beneficial effect on lipid parameters than ROSI. In order to get further insight into the lipid effects of both drugs, we tested whether PIO, compared to ROSI, could exert direct effects on lipid liver metabolism in relation with plasma lipids. Methods We performed in vitro studies using mice liver slices incubated 21 h either with ROSI (1 µmol/L) or PIO (7.5 µmol/L). Results We showed that both glitazones slightly reduced HMG-CoA reductase mRNA levels at the same degree but only PIO reduced intracellular cholesterol content, suggesting an alteration of cholesterol uptake rather than an inhibition of cholesterol biosynthesis. This concept was supported by the reduction of scavenger receptor class B type I expression, hepatic lipase activity and high-density lipoprotein cholesterol uptake in PIO-treated liver explants. Conversely, hepatic lipase mRNA levels were increased 3.5-fold. ROSI, but not PIO, induced acetyl-CoA carboxylase and fatty acid synthase gene expression and increased apoB secretion suggesting a stimulation of lipogenesis. Concurrently, peroxisome proliferator-activated receptor-, mRNA levels were induced by ROSI and not significantly changed by PIO. Besides, PIO appeared to be a more potent activator of AMP-Activated Protein Kinase than ROSI. Conclusions PIO and ROSI exert specific direct effects on liver and extrapolating these data to humans could explain the significant improvements in plasma lipids observed in diabetic patients treated with PIO. Copyright © 2010 John Wiley & Sons, Ltd. [source]

    Cover Picture (Isr. J. Chem.

    Structures of E. coli Adenylate Kinase in the open (4AKE) and closed (1ANK) states with cyanine dye derivatives modeled onto residues 128 and 194 for single-molecule Forster resonance energy transfer (FRET) studies of lid dynamics. The bottom of the figure displays a sample distance-vs.-time trajectory displaying spontaneous lid open,closed transitions on the millisecond timescale. The time-dependent potential of mean force along the lid coordinate measured by single-molecule FRET is also displayed. Further information can be found in Hanson et al., Proc. Natl. Acad. Sci. USA, 104, 18055,18060 (2007). With thanks to Haw Yang. [source]

    The Role of c-Jun N-Terminal Kinase (JNK) in Parkinson's Disease

    IUBMB LIFE, Issue 4-5 2003
    Jun Peng
    Abstract Given the critical role that the c-Jun N-terminal kinase (JNK) pathway plays in regulating many of the cellular processes which are affected in Parkinson's disease (PD), the possible importance of JNK in disease pathogenesis is being increasingly recognized. Here we review recent findings implicating the JNK signaling pathway in animal models of Parkinson's disease and discuss the relationship between this pathway and the prominent pathological processes observed in the disease state. We suggest that regulation of the JNK signaling pathway may be a central facet in potential treatments for the disease. IUBMB Life, 55: 267-271, 2003 [source]

    Myosin Light Chain Kinase as a Multifunctional Regulatory Protein of Smooth Muscle Contraction

    IUBMB LIFE, Issue 6 2001
    Ying Gao
    Abstract Myosin light chain kinase (MLCK) is a regulatory protein for smooth muscle contraction, which acts by phosphorylating 20-kDa myosin light chain (MLC20) to activate the myosin ATPase activity. Although this mode of action is well-established, there are numerous reports of smooth muscle contraction that is not associated with MLC20 phosphorylation. The kinase activity for the phosphorylation is localized at the central part of MLCK, which is also furnished with actin-binding activity at its N terminal and myosin-binding activity at its C terminal. This article overviews as to how such multifunctional properties of MLCK modify the actin-myosin interaction and presents our observations that the phosphorylation is not obligatory in induction of smooth muscle contraction. [source]

    Diosmetin Induces Human Osteoblastic Differentiation Through the Protein Kinase C/p38 and Extracellular Signal-Regulated Kinase 1/2 Pathway,

    Ya-Ling Hsu
    Abstract Introduction: The survival of osteoblasts is one of the determinants of the development of osteoporosis. This study is the first to investigate the osteoblastic differentiation induced by diosmetin, a flavonoid derivative, in osteoblastic cell lines MG-63, hFOB, and MC3T3-E1 and bone marrow stroma cell line M2-10B4. Materials and Methods: Osteoblastic differentiation was determined by assaying alkaline phosphatase (ALP) activity and mineralization degree and measuring various osteoblast-related markers using ELISA. Expression and phosphorylation of Runt-related transcription factor 2 (Runx2), protein kinase C, (PKC,), extracellular signal-regulated kinase (ERK), p38, and c- jun -N-terminal kinase (JNK) was assessed by immunoblot. Rac1 activity was determined by immunoprecipitation, and Runx2 activity was assessed by EMSA. Genetic inhibition was performed by small hairpin RNA plasmids or small interfering RNA (siRNA) transfection. Results: Diosmetin exhibited an effect on osteoblastic maturation and differentiation by means of ALP activity, osteocalcin, osteopontin, and type I collagen production, as well as Runx2 upregulation. Induction of differentiation by diosmetin was associated with increased PKC, phosphorylation and the activations of Rac1 and p38 and ERK1/2 kinases. Blocking PKC, by siRNA inhibition significantly decreased osteoblastic differentiation by inhibiting Rac1 activation and subsequently attenuating the phosphorylation of p38 and ERK1/2. In addition, blocking p38 and ERK1/2 by siRNA transfection also suppressed diosmetin-induced cell differentiation. Conclusions: In this study, we show that diosmetin induced osteoblastic differentiation through the PKC,-Rac1-MEK3/6-p38 and PKC,-Rac1-MEK1/2- ERK1/2-Runx2 pathways and that it is a promising agent for treating osteoporosis. [source]

    Negative Regulation by p70 S6 Kinase of FGF-2,Stimulated VEGF Release Through Stress-Activated Protein Kinase/c- Jun N-Terminal Kinase in Osteoblasts,

    Shinji Takai
    Abstract To clarify the mechanism of VEGF release in osteoblasts, we studied whether p70 S6 kinase is involved in basic FGF-2,stimulated VEGF release in osteoblast-like MC3T3-E1 cells. In this study, we show that p70 S6 kinase activated by FGF-2 negatively regulates VEGF release through SAPK/JNK in osteoblasts. Introduction: Vascular endothelial growth factor (VEGF) plays an important role in bone metabolism. We have previously reported that fibroblast growth factor-2 (FGF-2) stimulates the release of VEGF through p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c- Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells and that FGF-2,activated p38 MAP kinase negatively regulates VEGF release. However, the mechanism behind VEGF release in osteoblasts is not precisely known. Materials and Methods: The levels of VEGF released from MC3T3-E1 cells were measured by enzyme immunoassay. The phosphorylation of each protein kinase was analyzed by Western blotting. To knock down p70 S6 kinase in MC3T3-E1 cells, the cells were transfected with siRNA to target p70 S6 kinase. Results: FGF-2 time-dependently induced the phosphorylation of p70 S6 kinase. Rapamycin significantly enhanced the FGF-2,stimulated VEGF release and VEGF mRNA expression. The FGF-2,induced phosphorylation of p70 S6 kinase was suppressed by rapamycin. Rapamycin markedly enhanced the FGF-2,induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p44/p42 MAP kinase or p38 MAP kinase. SP600125, a specific inhibitor of SAPK/JNK, suppressed the amplification by rapamycin of the FGF-2,stimulated VEGF release similar to the levels of FGF-2 with SP600125. Finally, downregulation of p70 S6 kinase by siRNA significantly enhanced the FGF-2,stimulated VEGF release and phosphorylation of SAPK/JNK. Conclusions: These results strongly suggest that p70 S6 kinase limits FGF-2,stimulated VEGF release through self-regulation of SAPK/JNK, composing a negative feedback loop, in osteoblasts. [source]

    Osteoclast Differentiation by RANKL Requires NF-,B-Mediated Downregulation of Cyclin-Dependent Kinase 6 (Cdk6),

    Toru Ogasawara
    Abstract This study investigated the involvement of cell cycle factors in RANKL-induced osteoclast differentiation. Among the G1 cell cycle factors, Cdk6 was found to be a key molecule in determining the differentiation rate of osteoclasts as a downstream effector of the NF-,B signaling. Introduction: A temporal arrest in the G1 phase of the cell cycle is a prerequisite for cell differentiation, making it possible that cell cycle factors regulate not only the proliferation but also the differentiation of cells. This study investigated cell cycle factors that critically influence differentiation of the murine monocytic RAW264.7 cells to osteoclasts induced by RANKL. Materials and Methods: Growth-arrested RAW cells were stimulated with serum in the presence or absence of soluble RANKL (100 ng/ml). Expressions of the G1 cell cycle factors cyclin D1, D2, D3, E, cyclin-dependent kinase (Cdk) 2, 4, 6, and Cdk inhibitors (p18 and p27) were determined by Western blot analysis. Involvement of NF-,B and c- jun N-terminal kinase (JNK) pathways was examined by overexpressing dominant negative mutants of the I,B kinase 2 (IKKDN) gene and mitogen-activated protein kinase kinase 7 (MKK7DN) gene, respectively, using the adenovirus vectors. To determine the direct effect of Cdk6 on osteoclast differentiation, stable clones of RAW cells transfected with Cdk6 cDNA were established. Osteoclast differentiation was determined by TRACP staining, and cell cycle regulation was determined by BrdU uptake and flow cytometric analysis. Results and Conclusion: Among the cell cycle factors examined, the Cdk6 level was downregulated by RANKL synchronously with the appearance of multinucleated osteoclasts. Inhibition of the NF-,B pathway by IKKDN overexpression, but not that of the JNK pathway by MKK7DN overexpression, caused the decreases in both Cdk6 downregulation and osteoclastogenesis by RANKL. RAW cells overexpressing Cdk6 resist RANKL-induced osteoclastogenesis; however, cell cycle regulation was not affected by the levels of Cdk6 overexpression, suggesting that the inhibitory effect of Cdk6 on osteoclast differentiation was not exerted through cell cycle regulation. These results indicate that Cdk6 is a critical regulator of RANKL-induced osteoclast differentiation and that its NF-,B-mediated downregulation is essential for efficient osteoclast differentiation. [source]

    Possible Involvement of I,B Kinase 2 and MKK7 in Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor ,B Ligand,

    Aiichiro Yamamoto
    Abstract Recent studies have revealed the essential role of the receptor activator of nuclear factor ,B (NF-,B) ligand (RANKL) in osteoclast differentiation and activation. Adenovirus vector could efficiently transduce genes into RAW264.7 cells, which differentiate into osteoclast-like multinucleated cells in the presence of RANKL. The role of NF-,B and c- jun N-terminal kinase (JNK) activation in RANKL-induced osteoclast differentiation was investigated using an adenovirus vector carrying the dominant negative I,B kinase 2 gene (AxIKK2DN) or dominant negative MKK7 gene (AxMKK7DN). IKK2DN and MKK7DN overexpression in RAW cells specifically suppressed the NF-,B activation and JNK activation in response to RANKL, respectively, without affecting other signaling pathways. Either inhibition of NF-,B or JNK pathways dose-dependently inhibited osteoclast formation induced by RANKL. These results suggest that both NF-,B and JNK activation are independently required for osteoclast differentiation. [source]

    Basic Fibroblast Growth Factor Stimulates Vascular Endothelial Growth Factor Release in Osteoblasts: Divergent Regulation by p42/p44 Mitogen-Activated Protein Kinase and p38 Mitogen-Activated Protein Kinase

    Haruhiko Tokuda
    Abstract We previously showed that basic fibroblast growth factor (bFGF) activates p38 mitogen-activated protein (MAP) kinase via Ca2+ mobilization, resulting in interleukin-6 (IL-6) synthesis in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of bFGF on the release of vascular endothelial growth factor (VEGF) in these cells. bFGF stimulated VEGF release dose dependently in the range between 10 and 100 ng/ml. SB203580, an inhibitor of p38 MAP kinase, markedly enhanced the bFGF-induced VEGF release. bFGF induced the phosphorylation of both p42/p44 MAP kinase and p38 MAP kinase. PD98059, an inhibitor of upstream kinase of p42/p44 MAP kinase, reduced the VEGF release. SB203580 enhanced the phosphorylation of p42/p44 MAP kinase induced by bFGF. The enhancement by SB203580 of the bFGF-stimulated VEGF release was suppressed by PD98059. The depletion of extracellular Ca2+ by [ethylenebis-(oxyethylenenitrilo)]tetracetic acid (EGTA) or 1,2-bis-(O -aminophinoxy)-ethane- N,N,N,N -tetracetic acid tetracetoxymethyl ester (BAPTA/AM), a chelator of intracellular Ca2+, suppressed the bFGF-induced VEGF release. A23187, a Ca ionophore, or thapsigargin, known to induce Ca2+ release from intracellular Ca2+ store, stimulated the release of VEGF by itself. A23187 induced the phosphorylation of p42/p44 MAP kinase and p38 MAP kinase. PD98059 suppressed the VEGF release induced by A23187. SB203580 had little effect on either A23187-induced VEGF release or the phosphorylation of p42/p44 MAP kinase by A23187. These results strongly suggest that bFGF stimulates VEGF release through p42/p44 MAP kinase in osteoblasts and that the VEGF release is negatively regulated by bFGF-activated p38 MAP kinase. [source]

    A new era for small molecule screening: from new targets, such as JAK2 V617F, to complex cellular screens

    Stefan N. ConstantinescuArticle first published online: 21 JAN 200
    Traditionally reserved to research and development in pharmaceutical companies, screening of small molecule libraries is rapidly becoming an approach undertaken by academic laboratories. Novel cellular assays, sensitive systems to probe function, emerging new molecular targets are just some of the reasons explaining this shift. Targets of small molecules identified in cellular screens begin to be amenable to identification by elegant genetic approaches, such as probing toxicity of candidate small molecules on libraries of genetically modified yeast strains. Several new targets, such as JAK2 V617F, an activated JAK2 (Janus Kinase 2) mutant genetically associated with the majority of human myeloproliferative neoplasms, are being actively pursued. In this Review Series, we will learn how libraries of small molecules are harnessed to identify novel molecules, that alone or in combination, have the ability to alter cell fate, cell signalling, gene expression or response to extracellular cues. [source]

    Non-conventional signal transduction by type 1 interferons: The NF-,B pathway

    Ziyun Du
    Abstract Type I interferons (IFNs) regulate diverse cellular functions by modulating the expression of IFN-stimulated genes (ISGs) through the activation of the well established signal transduction pathway of the Janus Kinase (JAK) and signal transducers and activators of transcription (STAT) proteins. Although the JAK,STAT signal transduction pathway is critical in mediating IFN's antiviral and antiproliferative activities, other signaling pathways are activated by IFNs and regulate cellular response to IFN. The NF-,B transcription factor regulates the expression of genes involved in cell survival and immune responses. We have identified a novel IFN mediated signal pathway that leads to NF-,B activation and demonstrate that a subset of ISGs that play key roles in cellular response to IFN is regulated by NF-,B. This review focuses on the IFN-induced NF-,B activation pathway and the role of NF-,B in ISG expression, antiviral activity and apoptosis, and the therapeutic application of IFN in cancer and infectious disease. J. Cell. Biochem. 102: 1087,1094, 2007. © 2007 Wiley-Liss, Inc. [source]

    p75NTR -mediated signaling promotes the survival of myoblasts and influences muscle strength

    Shailaja Reddypalli
    During muscle development, the p75NTR is expressed transiently on myoblasts. The temporal expression pattern of the receptor raises the possibility that the receptor is influencing muscle development. To test this hypothesis, p75NTR -deficient mutant mice were tested for muscle strength by using a standard wire gripe strength test and were found to have significantly decreased strength relative to that of normal mice. When normal mybolasts were examined in vivo for expression of NGF receptors, p75NTR was detected on myoblasts but the high affinity NGF receptor, trk A, was not co-expressed with p75NTR. In vitro, proliferating C2C12 and primary myoblasts co-expressed the p75NTR and MyoD, but immunofluorescent analysis of primary myoblasts and RT-PCR analysis of C2C12 mRNA revealed that myoblasts were devoid of trk A. In contrast to the cell death functions that characterize the p75NTR in neurons, p75NTR -positive primary and C2C12 myoblasts did not differentiate or undergo apoptosis in response to neurotrophins. Rather, myoblasts survived and even proliferated when grown at subconfluent densities in the presence of the neurotrophins. Furthermore, when myoblasts treated with NGF were lysed and immunoprecipitated with antibodies against phosphorylated I-,B and AKT, the cells contained increased levels of both phospho-proteins, both of which promote cell survival. By contrast, neurotrophin-treated myoblasts did not induce phosphorylation of Map Kinase p42/44 or p38, indicating the survival was not mediated by the trk A receptor. Taken together, the data indicate that the p75NTR mediates survival of myoblasts prior to differentiation and that the activity of this receptor during myogenesis is important for developing muscle. © 2005 Wiley-Liss, Inc. [source]

    JNK signaling in insulin-producing cells is required for adaptive responses to stress in Drosophila

    AGING CELL, Issue 3 2009
    Jason Karpac
    Summary Adaptation to environmental challenges is critical for the survival of an organism. Repression of Insulin/IGF Signaling (IIS) by stress-responsive Jun-N-terminal Kinase (JNK) signaling is emerging as a conserved mechanism that allows reallocating resources from anabolic to repair processes under stress conditions. JNK activation in Insulin-producing cells (IPCs) is sufficient to repress Insulin and Insulin-like peptide (ILP) expression in rats and flies, but the significance of this interaction for adaptive responses to stress is unclear. In this study, it is shown that JNK activity in IPCs of flies is required for oxidative stress-induced repression of the Drosophila ILP2. It is found that this repression is required for growth adaptation to heat stress as well as adult oxidative stress tolerance, and that induction of stress response genes in the periphery is in part dependent on IPC-specific JNK activity. Endocrine control of IIS by JNK in IPCs is thus critical for systemic adaptation to stress. [source]

    p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL-1,

    Rebecca K. Studer
    Abstract Analysis of disc gene expression implicated IL-1 in the development of intervertebral disc degeneration (IDD) in a rabbit stab model. The purpose of these studies is to determine the role of p38 Mitogen Activated Protein Kinase (p38 MAPK) signaling in nucleus pulposus cell response to IL-1, and to compare rabbit nucleus pulposus (rNP) cell responses to IL-1 activation with those in a stab model of disc degeneration. NP cells maintained in alginate bead culture were exposed to IL-1, with or without p38 MAPK inhibition. RNA was isolated for reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression, conditioned media analyzed for accumulation of nitric oxide (NO) and prostaglandin E-2 (PGE-2), and proteoglycan synthesis measured after 10 days. IL-1 upregulation of mRNA for cycloxygenase-2 (COX-2), matrix metalloproteinase-3 (MMP-3), IL-1, and IL-6, was blunted by p38 inhibition while downregulation of matrix proteins (collagen I, collagen II, aggrecan) and insulin-like-growth-factor I (IFG-1) was also reversed. mRNA for tissue inhibitor of matrixmetalloproteinase-1 (TIMP-1) was modestly increased by IL-1, while those for Transforming Growth Factor-, (TGF-,) SOX-9, and versican remained unchanged. Blocking p38 MAPK reduced IL-1 induced NO and PGE-2 accumulation and partially restored proteoglycan synthesis. p38 MAPK inhibition in control cells increased mRNA for matrix proteins (aggrecan, collagen II, versican, collagen I) and anabolic factors (IGF-1, TGF, and SOX-9) from 50% to 120%, decreased basal PGE-2 accumulation, but had no effect on message for TIMP-1, MMP-3, or COX-2. Inhibition of p38 MAPK in cytokine-activated disc cells blunts gene expression and production of factors associated with inflammation, pain, and disc matrix catabolism while reversing IL-1 downregulation of matrix protein gene expression and proteoglycan synthesis. The results support the hypothesis that IL-1 could be responsible for many of the mRNA changes seen in rabbit NP in the stab model of disc degeneration, and uphold the concept that development of molecular techniques to block p38 MAPK could provide a therapeutic approach to slow the course of intervertebral disc degeneration. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:991,998, 2008 [source]

    Role of Dopamine D1 Receptors and Extracellular Signal Regulated Kinase in the Motivational Properties of Acetaldehyde as Assessed by Place Preference Conditioning

    ALCOHOLISM, Issue 4 2010
    Liliana Spina
    Background:, The role of dopamine D1 receptors and Extracellular signal Regulated Kinase (ERK) in the motivational properties of drugs can be studied by place-conditioning. Recent advances have shown that the motivational properties of ethanol, determined by place-conditioning, are mediated by its metabolic conversion into acetaldehyde. To date, the role of D1 receptors and ERK activation in acetaldehyde-elicited place preference has not been determined. The aim of this study was to assess the role of D1 receptors blockade and MEK inhibition in the acquisition of acetaldehyde-elicited conditioned place preference. Methods:, Male Sprague,Dawley rats were subjected to repeated pairings with 1 compartment of the conditioning apparatus immediately following acetaldehyde (20 mg/kg i.g.) or ethanol (1 g/kg i.g.) administration. The D1 receptor antagonist, SCH 39166 (50 ,g/kg s.c.), was administered 10 minutes before acetaldehyde or ethanol administration. In order to study the role of activated ERK in the acetaldehyde-elicited place preference, rats were administered the MEK inhibitor, PD98059 (1, 30, and 90 ,g i.c.v.), 10 or 30 minutes before acetaldehyde. To verify the specificity of these effects, we also studied whether PD98059 pretreatment could affect morphine (1 mg/kg s.c.)-elicited place preference. Results:, Both acetaldehyde and ethanol elicited significant place preferences and these were prevented by pretreatment with SCH 39166. In addition, pretreatment with PD98059, dose (30 and 90 but not 1 ,g i.c.v.) and time (10 but not 30 minutes before) dependently, prevented the acquisition of acetaldehyde- and significantly reduced the acquisition of morphine-elicited conditioned place preference. Conclusions:, These results confirm that acetaldehyde and ethanol elicit conditioned place preference and demonstrate that D1 receptors are critically involved in these effects. Furthermore, the finding that PD98059 prevents the acquisition of acetaldehyde-elicited conditioned place preference highlights the importance of the D1 receptor,ERK pathway in its motivational effects. [source]

    Ethanol Promotes Thiamine Deficiency-Induced Neuronal Death: Involvement of Double-Stranded RNA-activated Protein Kinase

    ALCOHOLISM, Issue 6 2009
    Zun-Ji Ke
    Background:, Heavy alcohol consumption causes cerebellar degeneration, and the underlying mechanism is unclear. Chronic alcoholism is usually associated with thiamine deficiency (TD) which is known to induce selective neurodegeneration in the brain. However, the role of TD in alcohol-induced cerebellar degeneration remains to be elucidated. The double-stranded RNA-activated protein kinase (PKR) is a potent antiviral protein. Viral infection or binding to dsRNA causes PKR autophosphorylation and subsequent phosphorylation of the ,-subunit of eukaryotic translation factor-2,, leading to inhibition of translation or apoptosis. PKR can also be activated by cellular stresses. Methods:, In this study, we used an in vitro model, cultured cerebellar granule neurons (CGNs), to investigate the interaction between TD and ethanol and evaluate the contribution of their interaction to neuronal loss. TD was induced by treatment with amprolium in association with ethanol. Cell viability was determined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay. PKR expression/phosphorylation and subcellular distribution was analyzed with immunoblotting and immunocytochemistry. Results:, Thiamine deficiency caused death of CGNs but ethanol did not. However, TD plus ethanol induced a much greater cell loss than TD alone. TD-induced PKR phosphorylation and ethanol exposure significantly promoted TD-induced PKR phosphorylation as well as its nuclear translocation. A selective PKR inhibitor not only protected CGNs against TD toxicity, but also abolished ethanol potentiation of TD-induced loss of CGNs. Conclusions:, Ethanol promoted TD-induced PKR activation and neuronal death. PKR may be a convergent protein that mediates the interaction between TD and ethanol. [source]

    Ethanol-Induced Extracellular Signal Regulated Kinase: Role of Dopamine D1 Receptors

    ALCOHOLISM, Issue 5 2009
    Federico Ibba
    Background:, Addictive drugs activate extracellular signal regulated kinase (ERK) in brain regions critically involved in their affective and motivational properties. The aim of this study was to demonstrate the ethanol-induced activation of ERK in the nucleus accumbens (Acb) and in the extended amygdala [bed nucleus of the stria terminalis lateralis (BSTL) and central nucleus of the amygdala (CeA)] and to highlight the role of dopamine (DA) D1 receptors in these effects. Methods:, Ethanol (0.5, 1, and 2 g/kg) was administered by gavage and ERK phosphorylation was determined in the nucleus Acb (shell and core), BSTL, and CeA by immunohistochemistry. The DA D1 receptor antagonist, SCH 39166 (SCH) (50 ,g/kg), was administered 10 minutes before ethanol (1 g/kg). Results:, Quantitative microscopic examination showed that ethanol, dose-dependently increased phospho-ERK immunoreactivity (optical and neuronal densities) in the shell and core of nucleus Acb, BSTL, and CeA. Pretreatment with SCH fully prevented the increases elicited by ethanol (1 g/kg) in all brain regions studied. Conclusions:, The results of this study indicate that ethanol, similar to other addictive drugs, activates ERK in nucleus Acb and extended amygdala via a DA D1 receptor-mediated mechanism. Overall, these results suggest that the D1 receptors/ERK pathway may play a critical role in the motivational properties of ethanol. [source]

    Increased Consumption but Not Operant Self-administration of Ethanol in Mice Lacking the RII, Subunit of Protein Kinase A

    ALCOHOLISM, Issue 5 2006
    Frank M. Ferraro III
    Background: Accumulating evidence indicates that adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) is involved in the neurobiological responses to ethanol. Previous reports indicate that mice lacking the RII, subunit of PKA (RII,,/,) voluntarily consume more ethanol than wild-type controls (RII,+/+) using 2-bottle testing procedures. Although such procedures primarily measure consummatory behavior, operant self-administration procedures allow analysis of consummatory as well as appetitive or "ethanol-seeking" behavior (i.e., lever pressing is required to gain access to the ethanol solution). Therefore, we determined whether the high ethanol consumption characteristic of RII,,/, mice would be complemented by increased appetitive ethanol-seeking behavior in an operant paradigm. Methods: RII,,/, (n=8) and RII,+/+ (n=8) mice were initially sucrose-faded until they were lever responding for nonsweetened ethanol (10, 14, and 18%). Following the self-administration testing, RII,+/+ and RII,,/, mice were given access to 2 bottles, one containing water and the other ethanol to replicate the voluntary ethanol drinking data previously from our laboratory. Finally, immediately after voluntary consumption all mice were again tested for self-administration of 10% ethanol. Alterations in the reinforcement schedule were also explored as RII,+/+ and RII,,/, mice were tested for self-administration of 10% ethanol at FR-3 and FR-5 schedules. Results: The RII,,/, mice displayed lower operant responding for ethanol and food reinforcement compared with RII,+/+ controls. However, this effect was driven by a significant increase in lever responses made by female RII,+/+ mice. When the excessive lever responses of the female RII,+/+ mice are accounted for, the RII,,/, mice show ethanol lever responses comparable to controls. Following operant self-administration testing, RII,,/, mice of both sexes consumed more ethanol solution compared with RII,+/+ mice during 2-bottle testing. Conclusions: Increased ingestion of ethanol by RII,,/, mice is likely the result of altered PKA activity within neuronal pathways that control ethanol-consummatory behaviors. Conversely, the RII, subunit of PKA appears not to play a critical role in neuronal pathways that regulate appetitive behaviors directed at obtaining ethanol. Finally, increased operant self-administration of food and ethanol by female wild-type mice was absent in female RII,,/, mice, suggesting that normal PKA signaling may be part of a general, and sex-dependent, mechanism involved with reinforcement-seeking behavior. [source]

    Acute Ethanol Inhibits Extracellular Signal,Regulated Kinase, Protein Kinase B, and Adenosine 3,:5,-Cyclic Monophosphate Response Element Binding Protein Activity in an Age- and Brain Region,Specific Manner

    ALCOHOLISM, Issue 4 2005
    L Judson Chandler
    Background: As little as a single episode of exposure of the developing brain to ethanol can result in developmental neuropathology and mental retardation. Extracellular signal,regulated kinases (ERKs), protein kinase B (PKB), and adenosine 3,:5,-cyclic monophosphate response element binding protein (CREB) are messenger molecules that play important roles in neuronal plasticity and survival. This study was undertaken to examine the effects of acute ethanol on ERK, PKB, and CREB activation in the brain. Methods: Immunoblot analysis was used to determine the effects of a 1-hr exposure of ethanol on levels of phospho-ERC in primary cortical cultures and in the cerebral cortex, hippocampus, and cerebellum of postnatal day 5 (PN5), postnatal day 21 (PN21), and adult rats. Results: In cortical cultures, ethanol (100 mM) significantly reduced activity-dependent activation of phospho-ERK, phospho-PKB, and phospho-CREB by approximately 50%. In PN5 rats, ethanol (3.5 g/kg) inhibited both phospho-ERK and phospho-PKB in the cerebral cortex and hippocampus but was without effect in the cerebellum. A similar brain region,specific inhibition of phospho-ERK was observed in PN21 rats, whereas in adult rats, ethanol inhibited phospho-ERK in all three brain regions. In contrast, ethanol had no effect on phospho-PKB in either PN21 or adult rats. Without exception, ethanol inhibited phospho-CREB in an identical brain region, and age-dependent manner as was observed for phospho-ERK. Finally, administration of the NMDA antagonist MK-801 (0.5 mg/kg) to PN5 rats had no effect on phospho-ERK or phospho-PKB levels in any brain region. Conclusion: The results demonstrate that acute ethanol inhibits ERK/PKB/CREB signaling in brain. This inhibition occurs in an age- and brain region,specific manner, with inhibition of PKB restricted to a time during the brain growth-spurt period. Furthermore, the lack of effect of MK-801 suggests that inhibition of NMDA receptors is unlikely to play a major role in binge ethanol inhibition of ERK/PKB/CREB signaling in vivo. [source]

    Abnormal Expression of p16INK4a, Cyclin D1, Cyclin-Dependent Kinase 4 and Retinoblastoma Protein in Gastric Carcinomas,

    Ichiro Kishimoto MD
    Abstract Background and Objectives The p16INK4a (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas. Mehtods Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases. Results Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P,=,0.009). Cyclin D1 (P,=,0.042) and CDK4 (P,=,0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P,=,0.022). The patients with p16+/pRb,/cyclin D1,/CDK4, or p16,/pRb+/cyclin D1,/CDK4, tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors. Conclusions The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis. J. Surg. Oncol. 2008;98:60,66. © 2008 Wiley-Liss, Inc. [source]

    Expression of Etk/Bmx Tyrosine Kinase in Intrahepatic Cholangiocarcinoma

    Linlang Guo MD
    Abstract Background Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx) plays an important role in the growth, differentiation, apoptosis, proliferation, and tumorigenicity of epithelial cells. The purpose of this study was to investigate the expression of Etk/Bmx in intrahepatic cholangiocarcinoma (ICC) and correlated the expression with clinicopathological parameters. Methods Fifty-seven cases of ICC were immunostained for Etk/Bmx, HCV NS5, PCNA, bcl-2, and NF-,B p65. Results Etk/Bmx expression was present in 19 (33.3%) of 57 ICC specimens and correlated with cell differentiation and survival rate but not closely with tumor size and lymph node metastasis. There was a significant difference of expression of either PCNA-LI or Bcl-2 between Etk/Bmx-positive and -negative cases (P,<,0.05). However, no statistically significant association was found between Etk/Bmx expression and presence of HCV-NS5 or NF-,B p65. Conclusions Our results indicate that Etk/Bmx may be involved in the development of ICC and be a predictor of poor prognosis for ICC. HCV infection and NF-,B appears unrelated to Etk/Bmx expression. J. Surg. Oncol. 2008;97:428,432. © 2008 Wiley-Liss, Inc. [source]

    A novel LRRK2 mutation in an Austrian cohort of patients with Parkinson's disease

    MOVEMENT DISORDERS, Issue 11 2007
    Dietrich Haubenberger MD
    Abstract To investigate the frequency of mutations in the Leucine-Rich Repeat Kinase 2 gene (LRRK2) in a sample of Austrian Parkinson's disease (PD) patients, we sequenced the complete coding region in 16 patients with autosomal dominant PD. Furthermore, we sequenced exons 31, 35, and 41 additionally in 146 patients with idiopathic PD and 30 patients with dementia with Lewy bodies. Furthermore, all 192 patients were screened for 21 putative LRRK2 mutations. While the most common mutation G2019S and the risk variant G2385R were not found in our samples, we detected a novel missense mutation (S973N) in a patient with familial, late-onset and dopa-responsive PD. © 2007 Movement Disorder Society [source]

    A CDPK type protein kinase is involved in rice SPS light modulation

    Gabriela C. Pagnussat
    A protein kinase activity that can phosphorylate and inactivate rice (Oryza sativa) sucrose-phosphate synthase (SPS; UDP-glucose: d -fructose-6-phosphate-2-glucosyl transferase, EC was measured in extracts prepared from leaves exposed to light-dark transitions. Enzyme activity present in extracts from dark leaves was about 5-fold higher than the activity in extracts from leaves that had been collected in the light. The protein kinase (named R-SPSK) was purified about 100-fold from dark leaves and its biochemical properties were studied. The micromolar dependence of Ca2+ exhibited by R-SPSK, and its response to calmodulin antagonists was similar to the properties associated with members of the plant Calcium-Dependent Protein Kinase (CDPK) family. Two modulators of SPS activity, Pi and Glc-6-P, were examined for an effect on R-SPSK. While Glc-6-P did not affect R-SPSK activity, Pi drastically increased the kinase activity. Taken together, these data provide evidence that SPS may be regulated by a CDPK type protein-kinase whose activity is modulated by light-dark transitions and stimulated by Pi, the negative effector of SPS activity. [source]

    Activation of MAP Kinase in Lumbar Spinothalamic Cells Is Required for Ejaculation

    Michael D. Staudt MSc
    ABSTRACT Introduction., Ejaculation is a reflex controlled by a spinal ejaculation generator located in the lumbosacral spinal cord responsible for the coordination of genital sensory with autonomic and motor outputs that regulate ejaculation. In the male rat, a population of lumbar spinothalamic cells (LSt cells) comprises an essential component of the spinal ejaculation generator. LSt cells are activated with ejaculation, but the nature of the signal transduction pathways involved in this activation is unknown. Moreover, it is unknown if LSt cell activation is required for expression of ejaculation. Aim., The current study tested the hypothesis that ejaculatory reflexes are triggered via activation of the mitogen-activated protein (MAP) kinase signaling pathway in the LSt cells. Methods., Expression of phosphorylated extracellular signal-related kinases 1 and 2 (pERK) was investigated following mating behavior, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intrathecal or intraspinal delivery of Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor U0126 on DPN stimulation-induced ejaculation was examined. Main Outcome Measures., Expression of pERK in LSt cells and associated areas was analyzed. Electromyographic recordings of the bulbocavernosus muscle were recorded in anesthetized, spinalized rats. Results., Results indicate that the MAP kinase signaling pathway is activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, ERK activation in LSt cells is an essential trigger for ejaculation, as DPN stimulation-induced reflexes were absent following administration of MEK inhibitor in the L3-L4 spinal area. Conclusion., These data provide insight into the nature of the signal transduction pathways involved in the activation of ejaculation through LSt cells. The data demonstrate that ERK activation in LSt cells is essential for ejaculation and contribute to a more detailed understanding of the spinal generation of ejaculation. Staudt MD, de Oliveira CVR, Lehman MN, McKenna KE, and Coolen LM. Activation of MAP kinase in lumbar spinothalamic cells is required for ejaculation. J Sex Med 2010;7:2445,2457. [source]

    Phosphorylation-Dependent Kinase,Substrate Cross-Linking,

    ANGEWANDTE CHEMIE, Issue 9 2010
    Sujit Suwal
    Die Identifizierung von Substraten für bestimmte Kinasen ist eine Voraussetzung für die Aufklärung zellulärer Signalkaskaden und wird hier mithilfe von kinasekatalysierter Markierung und Photovernetzung angegangen (siehe Schema). Bei Kopplung mit einer massenspektrometrischen Analyse können die Phosphorylierungsstellen sowie die ursächliche Kinase ermittelt werden. ADP=Adenosin-5,-diphosphat. [source]

    Cortistatin,A is a High-Affinity Ligand of Protein Kinases ROCK, CDK8, and CDK11,

    ANGEWANDTE CHEMIE, Issue 47 2009
    Antiproliferatives Alkaloid: Cortistatin,A ist ein hochaffiner Ligand für einen kleinen Satz von Proteinkinasen, einschließlich der Rho-assoziierten Proteinkinase (ROCK), der Cyclin-abhängigen Kinase,8 (CDK8) und der Cyclin-abhängigen Kinase,11 (CDK11). Modelle von Cortistatin,A im Komplex mit einer kristallographischen Struktur von ROCK (siehe Bild) und ein Homologiemodell von CDK8 werden präsentiert. [source]

    Antiviral gene expression in rheumatoid arthritis: Role of IKK, and interferon regulatory factor 3

    ARTHRITIS & RHEUMATISM, Issue 3 2007
    Susan E. Sweeney
    Objective The rheumatoid synovium displays characteristics of Toll-like receptor (TLR) activation and antiviral gene expression, including production of RANTES and interferon-, (IFN,). The mechanism of this activation in rheumatoid synovial tissue is unknown. This study was designed to investigate the role of the IKK-related kinase IKK, and IFN regulatory factor 3 (IRF-3) in the activation of antiviral genes in rheumatoid arthritis (RA). Methods Kinase assay and immunostaining were performed on synovial tissue. Dominant-negative (DN) IKK, adenoviral infection of human fibroblast-like synoviocytes (FLS) was followed by poly(I-C) stimulation and Western blotting. Quantitative polymerase chain reaction was performed on DN IKK,,infected FLS and IKK,,/, and IKK,+/+ mouse FLS. Results Western blotting showed that IKK, phosphorylation was significantly greater in RA synovium compared with osteoarthritis synovium. Kinase assay confirmed that IKK, was activated in RA synovium, and immunostaining showed localization of pIKK, to the intimal lining. Western blot analysis demonstrated that activation of IRF-3 was also increased in RA synovium. Poly(I-C), lipopolysaccharide, and tumor necrosis factor , (TNF,) activated phosphorylation of IKK, and IRF-3 in FLS. DN IKK, inhibited IRF-3 phosphorylation as well as RANTES and IFN, protein production in synoviocytes. Antiviral gene expression was also reduced in FLS from IKK,,/, mice compared with IKK,+/+ mice. Conclusion Antiviral gene expression in RA, especially due to TLR ligands and TNF,, is dependent on IKK, and IRF-3, and this pathway plays a key role in the production of type I IFNs and chemokines such as RANTES. These findings indicate that the IKK, pathway may have potential as a therapeutic target in RA. [source]

    5-Aminoimidazole-4-carboxamide-1-,- d -ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre-conditioning: Potential Role of AMP-Activated Protein Kinase

    Steen B. Kristiansen
    AMP-activated protein kinase (AMPK) is activated by exercise and 5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside (AICAR). Early pre-conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre-conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty-four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5-fold in AICAR-treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre-conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre-conditioning. [source]