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81.
Anika Mann Susann Illing Elke Miess Stefan Schulz 《British journal of pharmacology》2015,172(2):311-316
The efficiency of μ-opioid receptor signalling is tightly regulated and ultimately limited by the coordinated phosphorylation of intracellular serine and threonine residues. Here, we review and discuss recent progress in the generation and application of phosphosite-specific μ-opioid receptor antibodies, which have proved to be excellent tools for monitoring the spatial and temporal dynamics of receptor phosphorylation and dephosphorylation. Agonist-induced phosphorylation of μ-opioid receptors occurs at a conserved 10 residue sequence 370TREHPSTANT379 in the receptor''s carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at S375, present in the middle of this sequence, but only high-efficacy opioids have the ability to drive higher order phosphorylation on flanking residues (T370, T376 and T379). S375 is the initiating residue in a hierarchical phosphorylation cascade. In contrast, agonist-independent heterologous μ-opioid receptor phosphorylation occurs primarily at T370. The combination of phosphosite-specific antibodies and siRNA knockdown screening also facilitated the identification of relevant kinases and phosphatases. In fact, morphine induces a selective S375 phosphorylation that is predominantly catalysed by GPCR kinase 5 (GRK5), whereas multisite phosphorylation induced by high-efficacy opioids specifically requires GRK2/3. By contrast, T370 phosphorylation stimulated by phorbol esters or heterologous activation of Gq-coupled receptors is mediated by PKCα. Rapid μ-opioid receptor dephosphorylation occurs at or near the plasma membrane and is catalysed by protein phosphatase 1γ (PP1γ). These findings suggest that there are distinct phosphorylation motifs for homologous and heterologous regulation of μ-opioid receptor phosphorylation. However, it remains to be seen to what extent different μ-opioid receptor phosphorylation patterns contribute to the development of tolerance and dependence in vivo.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 相似文献82.
Modulation of insulin action 总被引:10,自引:0,他引:10
Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. Insulin acts by binding to its cell surface receptor, thus activating the receptors intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and phosphorylation of several substrates. Tyrosine phosphorylated residues on the receptor itself and on subsequently bound receptor substrates provide docking sites for downstream signalling molecules, including adapters, protein serine/threonine kinases, phosphoinositide kinases and exchange factors. Collectively, those molecules orchestrate the numerous insulin-mediated physiological responses.A clear picture is emerging of the way in which insulin elicits several intracellular signalling pathways to mediate its physiologic functions. A further challenge, being pursued by several laboratories, is to understand the molecular mechanisms that underlie insulin action at the peripheral level, deregulation of which ultimately leads to hyperglycaemia and Type 2 diabetes.We review how circulating factors such as insulin itself, TNF-, interleukins, fatty acids and glycation products influence insulin action through insulin signalling molecules themselves or through other pathways ultimately impinging on the insulin-signalling pathway. Understanding how the mechanism by which molecular insulin action is modulated by these factors will potentially provide new targets for pharmacological agents, to enable the control of altered glucose and lipid metabolism and diabetes.Abbreviations AMPK
Adenosine 5-monophosphate-activated protein kinase
- Erk1/2
extracellular regulated kinase 1 and 2
- GSK-3
glycogen synthase kinase 3
- IKK
inhibitor kappa B kinase
- IR
insulin receptor
- JAKs
janus kinases
- JNK
jun amino terminal kinase
- MAPK
mitogen activated protein kinase
- PI3K
phosphoinositide 3-kinase
- PKB
protein kinase B
- PKC
protein kinase C
- S/T
serine/threonine
- SOCS
suppressor of cytokine signalling
- TOR
target of rapamycin 相似文献
83.
The mechanism for tension prolongation during reoxygenation following myocardial hypoxia was investigated. It was found that prior addition of isoproterenol, reserpine, quinidine, lidocaine and insulin or a change in pH, temperature, stimulation rate, preload or duration of hypoxia did not qualitatively alter the appearance of the phenomenon. On reoxygenating hypoxic preparations in the presence of 5, 10 or 20% oxygen, tension prolongation was clearly present when little increase in isometric tension was evident. Inhibition of glycolysis by iodoacetate did not alter the appearance of the phenomenon during reoxygenation. Three respiratory inhibitors, antimycin A, rotenone and cyanide, at concentrations which did not prevent an increase in isometric tension during recovery from myocardial hypoxia, all completely prevented the appearance of tension prolongation. Two uncouplers of oxidative phosphorylation, 2–4 dinitrophenol and carbonyl cyanide m-chlorophenyl hydrazone at concentrations large enough to lead to mechanical deterioration despite the presence of oxygen, failed to prevent the appearance of tension prolongation upon reoxygenation. It is concluded that myocardial respiratory activity, independent of ability to generate high energy phosphate, appears capable of altering the duration of mechanical events during reoxygenation of hypoxic heart muscle. 相似文献
84.
Alain P. Gobert Olivier Boutaud Mohammad Asim Irene A. Zagol-Ikapitte Alberto G. Delgado Yvonne L. Latour Jordan L. Finley Kshipra Singh Thomas G. Verriere Margaret M. Allaman Daniel P. Barry Kara M. McNamara Johanna C. Sierra Venkataraman Amarnath Mohammed N. Tantawy Diane Bimczok M. Blanca Piazuelo M. Kay Washington Keith T. Wilson 《Gastroenterology》2021,160(4):1256-1268.e9
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85.
86.
Teresa Rodríguez-Martín Inmaculada Cuchillo-Ibáñez Wendy Noble Fanon NyenyaBrian H. Anderton Diane P. Hanger 《Neurobiology of aging》2013
Phosphorylated forms of microtubule-associated protein tau accumulate in neurofibrillary tangles in Alzheimer's disease. To investigate the effects of specific phosphorylated tau residues on its function, wild type or phosphomutant tau was expressed in cells. Elevated tau phosphorylation decreased its microtubule binding and bundling, and increased the number of motile tau particles, without affecting axonal transport kinetics. In contrast, reducing tau phosphorylation enhanced the amount of tau bound to microtubules and inhibited axonal transport of tau. To determine whether differential tau clearance is responsible for the increase in phosphomimic tau, we inhibited autophagy in neurons which resulted in a 3-fold accumulation of phosphomimic tau compared with wild type tau, and endogenous tau was unaffected. In autophagy-deficient mouse embryonic fibroblasts, but not in neurons, proteasomal degradation of phosphomutant tau was also reduced compared with wild type tau. Therefore, autophagic and proteasomal pathways are involved in tau degradation, with autophagy appearing to be the primary route for clearing phosphorylated tau in neurons. Defective autophagy might contribute to the accumulaton of tau in neurodegenerative diseases. 相似文献
87.
88.
《Journal of neurogenetics》2013,27(2):118-122
Abstract:In the past three decades, efforts to understand the molecular mechanisms underlying photoreceptor transduction of the fruit fly Drosophila melanogaster experienced drastic waves of technological development that involve multiple areas of scientific disciplines; the multidisciplinary approach includes a classical genetic manipulation in which random mutations are created and phenotypes are screened, a modern genetics maneuver in which a specific gene relevant to a hypothesis is molecularly cloned and manipulated, and, more recently, direct studies of proteins by proteomics technologies in combination with modern molecular biology and electrophysiology. This paper will review efforts that originated three decades ago in Professor William L. Pak's laboratory at Purdue University to study proteins involved in the Drosophila photoreceptor transduction process and show the power of such multidisciplinary approach that involves collaboration between molecular genetics, electrophysiology, and proteomics. 相似文献
89.
Richard M. Gallo 《Growth factors (Chur, Switzerland)》2013,31(5):329-333
Phosphorylation state specific antibodies are important reagents for characterizing protein phosphorylation and signaling. However, these antibodies require proper validation to determine that they do not cross-react with the unphosphorylated peptide or with other phosphoproteins. We have previously shown that phosphorylation of tyrosine1056 of ErbB4 is critical for it to inhibit colony formation on plastic by human tumor cell lines. Thus, an antibody directed against this site would be useful for studying ErbB4 signaling and coupling to biological responses. Here, we demonstrate that a commercially available antibody raised against a phosphopeptide corresponding to the carboxyl-terminal domain of the ErbB4 receptor tyrosine kinase fails to exhibit appropriate specificity. Thus, this antibody does not appear to be suitable for studying ErbB4 phosphorylation or signaling. 相似文献
90.
Yan Xiong Xiao-Peng Jing Xin-Wen Zhou Xiu-Lian Wang Yang Yang Xu-Ying Sun Mei Qiu Fu-Yuan Cao You-Ming Lu Rong Liu Jian-Zhi Wang 《Neurobiology of aging》2013
The activity of protein phosphatase (PP) 2A is downregulated and promotes the hyperphosphorylation of tau in the brains of Alzheimer's disease (AD), but the mechanism for PP2A inactivation has not been elucidated. We have reported that PP2A phosphorylation at tyrosine 307 (Y307) is involved in PP2A inactivation. Here, we further studied the upstream mechanisms for PP2A phosphorylation and inactivation. We found that zinc, a heavy metal ion that is widely distributed in the normal brain and accumulated in the susceptible regions of AD brain, could induce PP2A inhibition, phosphorylation of PP2A at Y307 and tau hyperphosphorylation both in rat brains and cultured N2a cells, while zinc chelating prevented these changes completely. Upregulation of PP2A chemically or genetically attenuated zinc-induced tau hyperphosphorylation, whereas mutation of Y307 to phenylalanine abolished the zinc-induced tyrosine phosphorylation and inactivation of PP2A. Zinc could activate Src, while PP2, a specific Src family kinases inhibitor, attenuated zinc-induced PP2A phosphorylation and inactivation, indicating that zinc induces PP2A Y307 phosphorylation and inactivation through Src activation. In human tau transgenic mice, zinc chelator rescued PP2A activity, prevented Src activation, and reduced hyperphosphorylated and insoluble tau levels. We concluded that zinc induces PP2A inactivation and tau hyperphosphorylation through Src-dependent pathway, regulation of zinc homeostasis may be a promising therapeutic for AD and the related tauopathies. 相似文献