Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ca2(+)-mobilizing second messenger D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) is converted to the putative messenger D-myo-inositol 1,3,4,5-tetrakisphosphate by Ins(1,4,5)P3 3-kinase. We found that cAMP-dependent protein kinase and protein kinase C phosphorylate, and thereby modulate, the activity of Ins(1,4,5)P3 3-kinase. cAMP-dependent kinase introduced a stoichiometric amount of phosphate at serine 109 of the 53-kDa polypeptide and caused a 1.8-fold increase in Vmax, whereas the protein kinase C-dependent phosphorylation reduced the Vmax to one-fourth of that of the unphosphorylated enzyme. Upon prolonged incubation, protein kinase C introduced phosphate at multiple sites in Ins(1,4,5)P3 3-kinase, and the resulting inactivation of the enzyme appeared to be well-correlated with the simultaneous phosphorylation of two major sites, serine 109 and serine 175. The Km for Ins(1,4,5)P3 was not affected significantly after phosphorylation by either protein kinase. We propose, therefore, that the phosphorylation of Ins(1,4,5)P3 3-kinase by cAMP-dependent kinase and protein kinase C constitutes mechanisms of cross-talk between cellular signaling pathways that use various second messengers such as inositol phosphates, diacylglycerol, Ca2+, and cAMP.
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PMID:Regulation of D-myo-inositol 1,4,5-trisphosphate 3-kinase by cAMP-dependent protein kinase and protein kinase C. 216 47

The identification of the initial signaling events induced by progesterone in Xenopus oocyte maturation was approached by expressing serotonin receptors and by using pharmacological agents. Suppression of phospholipase C (PLC) activity in oocytes by U-73122 or stimulation of oocyte adenylyl cyclase (ACase) by forskolin inhibited progesterone-induced reinitiation of meiotic cell division. Microinjection of cAMP-dependent protein kinase (PKA) pseudosubstrate, PKI, into oocytes--or pretreatment of oocytes with PKA inhibitor, H-89--did not induce oocyte maturation, but both treatments potentiated the rate of progesterone-induced germinal vesicle breakdown (GVBD). In addition, reduced PKA activity by H-89 reversed the inhibition of GVBD caused by U-73122. Expression and activation of the serotonin receptor type 1a or type 2c lowered intracellular cAMP level or mobilized Ins(1,4,5)P3, respectively. These oocytes, however, did not undergo maturation upon serotonin stimulation. Co-expression of these receptors also did not trigger maturation, but it significantly accelerated the rate of GVBD induced by progesterone. From these data, we conclude that (1) changes in levels of these second messengers may well be coupled with progesterone signaling; (2) an initial decrease in cAMP and production of Ins(1,4,5)P3/DG may not be absolute requisites for progesterone-induced meiotic maturation: (3) cross-talk mechanisms between adenylyl cyclase and phosphoinositide signal transduction pathways may exist in the process of progesterone-induced reinitiation of meiotic cell cycle.
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PMID:Inhibition of the adenylyl cyclase and activation of the phosphatidylinositol pathway in oocytes through expression of serotonin receptors does not induce oocyte maturation. 943 51

Agonist-receptor interactions regulate airway smooth muscle tone through activation of guanine nucleotide binding proteins (G proteins), which are coupled to second messenger pathways that mediate changes in the tissue's contractile state. With respect to airway smooth muscle (ASM) contraction, receptor activation elicits phosphatidylinositol turnover that results in the formation of the second messengers, 1,2,-diacylglyserol, which activates protein kinase C (PKC), and inositol 1,4,5,-trisphosphate (Ins[1,4,5]P3), which binds to its intracellular receptor to mobilize intracellular calcium (Ca2+). Both the mobilization of Ca2+ and activation PKC play critical roles in initiating and acutely modulating the intensity and duration of the ASM contraction response. In contrast, bronchodilator agonist-mediated receptor activation is typically coupled to an enhanced accumulation of the second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) which, through activation of cAMP-dependent protein kinase, induces the phosphorylation of specific proteins, leading to ASM relaxation. For activation of both of these functionally distinct signal transduction pathways, the agonist-receptor complexes interact with specific G proteins, which in turn modulate the enzymes regulating the production of their respective second messengers. Perturbations in Ins(1,4,5)P3 accumulation, its metabolism and intracellular binding may underlie changes in ASM contractility. Comparably, changes in ASM relaxation responsiveness, secondary to perturbations in cAMP accumulation, may be due to altered receptor/G protein modulation of adenylate cyclase activity, as well as to altered binding of Ins(1,4,5)P3 to its Ca2+-mobilizing intracellular receptor. This review begins with an overview of the structural and functional characteristics of G protein-linked receptors, followed by descriptions of the role of G proteins, their transmembrane signaling processes, and mechanisms regulating second messenger-coupled ASM contraction and relaxation, and concludes with new information underscoring the important roles of altered receptor/G protein-coupled expression and regulatory interactions between signaling pathways in modulating second-messenger accumulation and action in the "pro-asthmatic" sensitized airway smooth muscle.
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PMID:Regulation of second messengers associated with airway smooth muscle contraction and relaxation. 981 34

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are calcium channels modulating important calcium-mediated processes. Recent studies implicate IP(3)R in cell metabolism, but specific evidence is missing regarding IP(3)R's effects on actual metabolic pathways and key energy metabolites. Here, we applied metabolomics and molecular biology to compare DT40 cell lines devoid of IP(3)R (KO) and its wild-type (WT) counterpart. NMR and LC-MS metabolomic data showed that the KO cell line has a very different basic energy metabolism from the WT cell line, showing enhanced Warburg effect. In particular, the KO cells exhibited significant perturbation in energy charge, reduced glutathione and NADPH ratios with slower cellular growth rate. Subsequent flow cytometry results showed that the KO cell line has a higher level of general reactive oxygen species (ROS) but has a lower level of peroxynitrites. This ROS disturbance could be explained by observing lower expression of superoxide dismutase 2 (SOD2) and unchanged expression of catalase. The higher ROS seems to be involved in the slower growth rate of the KO cells, with an ROS scavenger increasing their growth rate. However, the KO and WT cell lines did not show any noticeable differences in AMPK and phosphorylated AMPK levels, suggesting possible saturation of AMPK-mediated metabolic regulatory circuit in both cells. Overall, our study reveals IP3R's roles in ROS homeostasis and metabolic pathways as well as the effects of its KO on cellular phenotypes.
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PMID:The roles of IP3 receptor in energy metabolic pathways and reactive oxygen species homeostasis revealed by metabolomic and biochemical studies. 2623 38