The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Nikita Gamper - One of the best experts on this subject based on the ideXlab platform.
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reactive oxygen species are Second Messengers of neurokinin signaling in peripheral sensory neurons
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: John E Linley, Lezanne Ooi, Louisa Pettinger, Hannah M Kirton, John P Boyle, Chris Peers, Nikita GamperAbstract:Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and Gi/o proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as Second Messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca2+ stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca2+ stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.
Urs Jenal - One of the best experts on this subject based on the ideXlab platform.
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Reciprocal growth control by competitive binding of nucleotide Second Messengers to a metabolic switch in Caulobacter crescentus
Nature Microbiology, 2020Co-Authors: Viktoriya Shyp, Badri Nath Dubey, Raphael Böhm, Johannes Hartl, Jutta Nesper, Julia A. Vorholt, Sebastian Hiller, Tilman Schirmer, Urs JenalAbstract:Bacteria use small signalling molecules such as (p)ppGpp or c-di-GMP to tune their physiology in response to environmental changes. It remains unclear whether these regulatory networks operate independently or whether they interact to optimize bacterial growth and survival. We report that (p)ppGpp and c-di-GMP reciprocally regulate the growth of Caulobacter crescentus by converging on a single small-molecule-binding protein, SmbA. While c-di-GMP binding inhibits SmbA, (p)ppGpp competes for the same binding site to sustain SmbA activity. We demonstrate that (p)ppGpp specifically promotes Caulobacter growth on glucose, whereas c-di-GMP inhibits glucose consumption. We find that SmbA contributes to this metabolic switch and promotes growth on glucose by quenching the associated redox stress. The identification of an effector protein that acts as a central regulatory hub for two global Second Messengers opens up future studies on specific crosstalk between small-molecule-based regulatory networks. Crosstalk between small-molecule regulated networks controls growth in Caulobacter crescentus .
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Reciprocal growth control by competitive binding of nucleotide Second Messengers to a metabolic switch in Caulobacter crescentus.
Nature microbiology, 2020Co-Authors: Viktoriya Shyp, Badri Nath Dubey, Raphael Böhm, Johannes Hartl, Jutta Nesper, Julia A. Vorholt, Sebastian Hiller, Tilman Schirmer, Urs JenalAbstract:Bacteria use small signalling molecules such as (p)ppGpp or c-di-GMP to tune their physiology in response to environmental changes. It remains unclear whether these regulatory networks operate independently or whether they interact to optimize bacterial growth and survival. We report that (p)ppGpp and c-di-GMP reciprocally regulate the growth of Caulobacter crescentus by converging on a single small-molecule-binding protein, SmbA. While c-di-GMP binding inhibits SmbA, (p)ppGpp competes for the same binding site to sustain SmbA activity. We demonstrate that (p)ppGpp specifically promotes Caulobacter growth on glucose, whereas c-di-GMP inhibits glucose consumption. We find that SmbA contributes to this metabolic switch and promotes growth on glucose by quenching the associated redox stress. The identification of an effector protein that acts as a central regulatory hub for two global Second Messengers opens up future studies on specific crosstalk between small-molecule-based regulatory networks.
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bacterial signal transduction by cyclic di gmp and other nucleotide Second Messengers
Journal of Bacteriology, 2016Co-Authors: Regine Hengge, Urs Jenal, Robert P Ryan, Angelika Grundling, Fitnat H. YildizAbstract:ABSTRACT The first International Symposium on c-Di-GMP Signaling in Bacteria (22 to 25 March 2015, Harnack-Haus, Berlin, Germany) brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide Second messenger signaling. While the focus was on signal input, synthesis, degradation, and the striking diversity of the modes of action of the current Second messenger paradigm, i.e., cyclic di-GMP (c-di-GMP), “classics” like cAMP and (p)ppGpp were also presented, in novel facets, and more recent “newcomers,” such as c-di-AMP and c-AMP-GMP, made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters, and in the lively discussions, including (i) c-di-GMP control of the activities of various ATPases and phosphorylation cascades, (ii) extensive cross talk between c-di-GMP and other nucleotide Second messenger signaling pathways, and (iii) a stunning number of novel effectors for nucleotide Second Messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that Second messenger signaling is currently one of the most dynamic fields within molecular microbiology, with major impacts in research fields ranging from human health to microbial ecology.
Xue Hong Cao - One of the best experts on this subject based on the ideXlab platform.
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complex regulation of capsaicin on intracellular Second Messengers by calcium dependent and independent mechanisms in primary sensory neurons
Neuroscience Letters, 2012Co-Authors: Jie Wen Zhang, Yi Zhang, Xiang Gao, Xi Sheng Yan, Zhiguo Liu, Lie Ju Liu, Xue Hong CaoAbstract:Intracellular Second Messengers play an important role in capsaicin- and analogous-induced sensitization and desensitization in pain. Fluorescence Ca²⁺ imaging, enzyme immunoassay and PKC assay kit were used to determine a novel mechanism of different Ca²⁺ dependency in the signal transduction of capsaicin-induced desensitization. On the average, capsaicin increased cAMP, cGMP concentration and SP release in bell-shaped concentration-dependent manner, with the maximal responses at concentrations around 1 μM, suggesting acute desensitization of TRPV1 receptor activation. Capsaicin-induced intracellular Ca²⁺ concentration ([Ca²⁺](i)) increase depended on extracellular Ca²⁺ influx as an initial trigger. The Ca²⁺ influx by capsaicin increased PKC activation and SP release. These increases were completely abolished in Ca²⁺-free solution, suggesting that the modulation of capsaicin on PKC and SP are Ca²⁺-dependent. Interestingly, the maximal cAMP increase by TRPV1 activation was not blocked Ca²⁺ removal, suggesting at least in part a Ca²⁺-independent pathway is involved. Further study showed that cAMP increase was totally abolished by G-protein and adenylate cyclase (AC) antagonist, suggesting a G-protein-dependent pathway in cAMP increase. However, SP release was blocked by inhibiting PKC, but not G-protein or AC, suggesting a G-protein independent pathway in SP release. These results suggest that both Ca²⁺-dependent and independent mechanisms are involved in the regulation of capsaicin on Second Messengers systems, which could be a novel mechanism underlying distinct desensitization of capsaicin and might provide additional opportunities in the development of effective analgesics in pain treatment.
Yusuf A. Hannun - One of the best experts on this subject based on the ideXlab platform.
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Chapter 21 Lipids as Second Messengers
Principles of Medical Biology, 1997Co-Authors: Yusuf A. HannunAbstract:Summary Normal physiology demands that various cell types in the human body interact productively with other cell types and respond to various stimuli from their environment. These stimuli instruct the target cell types to perform specific functions such as hormone release, granule secretion, modulation of intermediary metabolism, reaction to infections and tissue injury, cell division and multiplication, cell differentiation, or cell death. These instructions are translated within the target cell types through the process of signal transduction which involves a number of biochemical reactions that are turned on by the extracellular stimuli, and in turn lead to modification of cell function (see Figure 3 for an example on platelet function). Membrane lipids have emerged as key components in this signal transduction pathway with products of lipid metabolism serving as important Second Messengers that are generated in response to extracellular stimuli. These lipid Second Messengers interact with specific biochemical targets such as protein kinases and phosphatases, as well as with metabolic enzymes, thus launching a cascade of intracellular changes. Diacylglycerol is the best studied and documented lipid Second messenger. Its levels are increased transiently in response to a number of growth factors and hormones. This elevation in diacylglycerol levels results in activation of the protein kinase C family of enzymes which serve as switches in regulation of cell function through the phosphorylation of a number of cellular protein substrates. Other lipids and lipid-derived molecules also are emerging as potential Second Messengers. Derangements in these signal transduction pathways involving lipid precursors, lipid-metabolizing enzymes, lipid Second Messengers, and targets of lipid Second Messengers may underlie diverse pathologic conditions including cancer, autoimmune disorders, inflammatory conditions, and cell senescence and cell death.
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Sphingolipid Second Messengers: Tumor Suppressor Lipids
Advances in experimental medicine and biology, 1997Co-Authors: Yusuf A. HannunAbstract:Although lipids play a critical role in membrane formation by providing the structural backbone for cellular and organeller membranes, a functional role for lipids in cell regulation is emerging. This is clearly established for membrane glycerolipids which play critical roles in signal transduction through the generation of important metabolic products (such as diacylglycerol, inositol trisphosphate, and eicosanoids) which function as Second Messengers. The phosphatidylinositol (PI) cycle provides the most compelling paradigm for the involvement of membrane lipids in signal transduction. On the other hand, an analogous role for membrane sphingolipids in signal transduction has not been defined. Sphingolipids demonstrate significant structural diversity and complexity even exceeding that of glycerolipids, with multiple biologic activities and functions attributed to these molecules (1–3). The discovery of the inhibition of protein kinase C by sphingosine raised the possibility that sphingosine and other sphingolipid-derived molecules may function as Second Messengers (2). Indeed, studies over the last few years have begun to elucidate a sphingolipid signal transduction pathway involving the hydrolysis of sphingomyelin (SM) and the generation of ceramide, in what has been termed the sphingomyelin cycle. This chapter will highlight our current understanding of the regulation of the SM cycle, and will concentrate on more recent insight into the Second messenger function of ceramide and its mechanism of action. A hypothesis suggesting a role for ceramide as a tumor suppressor lipid will be discussed.
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role of phospholipase in generating lipid Second Messengers in signal transduction
The FASEB Journal, 1991Co-Authors: Edward A Dennis, Sue Goo Rhee, Motasim M Billah, Yusuf A. HannunAbstract:Many lipids or lipid-derived products generated by phospholipases acting on phospholipids in membranes are implicated as mediators and Second Messengers in signal transduction. Our current understanding of the primary sequence relationships within the class of extracellular phospholipase A2's and among the numerous forms of the mammalian phosphatidylinositol-specific phospholipase C's is reviewed. New results suggesting roles for these phospholipases as well as other phospholipases such as phospholipase C and D acting on phosphatidlycholine in generating arachidonic acid for eicosanoid biosynthesis, inositol phosphates for Ca2+ mobilization, and diglyceride for protein kinase C activation through receptor-mediated processes, are discussed. In addition, the possible role of phospholipases acting on sphingolipids such as sphinglomyelinase in generating lipid mediators is considered.
D L Severson - One of the best experts on this subject based on the ideXlab platform.
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signal transduction in vascular smooth muscle diacylglycerol Second Messengers and pkc action
American Journal of Physiology-cell Physiology, 1994Co-Authors: M W Lee, D L SeversonAbstract:Agonist-stimulated phospholipid turnover can generate diacylglycerol (DAG), an intracellular Second messenger that activates protein kinase C (PKC). DAG can be produced from the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by a phosphoinositide-specific phospholipase C and by the degradation of phosphatidylcholine (PC) by a phospholipase C or the concerted actions of phospholipase D and phosphatidate phosphohydrolase. In vascular smooth muscle, agonist-stimulated DAG accumulation is biphasic; PIP2 hydrolysis produces a transient increase in DAG, which is followed by a sustained phase of DAG accumulation from PC degradation. Metabolism of DAG attenuates PKC activation and thus results in signal termination. The metabolic fates for DAG include 1) ATP-dependent phosphorylation to form phosphatidic acid (DAG kinase), 2) hydrolysis to release fatty acids and glycerol (DAG and monoacylglycerol lipases), 3) synthesis of triacylglycerol (DAG acyltransferase), and 4) synthesis of PC (choline phosphotransferase). Hydrolysis through the lipase pathway is the predominant metabolic fate of DAG in vascular smooth muscle. Activation of PKC in vascular smooth muscle modulates agonist-stimulated phospholipid turnover, produces an increase in contractile force, and regulates cell growth and proliferation. Further research is required to investigate cross talk between signal transduction mechanisms involving lipid Second Messengers. In addition, spatial considerations such as nuclear PKC activation and the influence of diradylglycerol generation on the duration of PKC activation are important issues.
