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A synaptic protein, Ca2+/Calmodulin dependent protein kinase II (CaMKII), has complex state transitions and facilitates the emergence of long term potentiation (LTP), which is highly correlated to memory formation. Two of the stat...
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A synaptic protein, Ca2+/Calmodulin dependent protein kinase II (CaMKII), has complex state transitions and facilitates the emergence of long term potentiation (LTP), which is highly correlated to memory formation. Two of the state transitions are critical for LTP: (1) threonine 286 autophosphorylation of CaMKII; and (2) binding to N-methyl-D-aspartate receptor (NMDAR) in the postsynaptic density (PSD) to form CaMKII-NMDAR complex. Both of these state transitions retain the activity of CaMKII when the induction signal disappears which is very important for the long-lasting characteristics of LTP. However, the possible relationships between the state transitions in the emergence of LTP are not well understood. We develop a mathematical model of the formation of CaMKII-NMDAR complex with the full state transitions of CaMKII, including the autophosphorylation, based on ordinary differential equations. In addition, we formulate a probabilistic framework for the binding between CaMKII and NMDAR. The model gives accurate predictions of the behaviours of CaMKII in comparisons to the experimental observations. Using the model, we show that: (1) the formation of CaMKII-NMDAR complex is dependent not only on the binding affinity between CaMKII and NMDAR, but also on the translocation of CaMKII into PSD; and (2) the autophosphorylation is not a requirement for the formation of CaMKII-NMDAR complex, but is important for the rapid formation of CaMKII-NMDAR complex during LTP. (C) 2014 Elsevier Ltd. All rights reserved.
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The present study was performed to investigate the effects of Ca 2+/calmodulin-dependent protein kinase II (CaMKII) antisense oligodeoxynucleotides (ODNs) on the assembly of the CaMKII?GluR6?PSD- 95 signaling module, GluR6 serine ...
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The present study was performed to investigate the effects of Ca 2+/calmodulin-dependent protein kinase II (CaMKII) antisense oligodeoxynucleotides (ODNs) on the assembly of the CaMKII?GluR6?PSD- 95 signaling module, GluR6 serine phosphorylation and c-Jun N-terminal kinase 3 (JNK3) activation. A further aim was to determine the neuroprotective mechanism of CaMKII antisense ODNs against ischemia-reperfusion (I/R)-induced neuronal death in the rat hippocampus. CaMKII antisense ODNs were intracerebroventricularly infused to inhibit CaMKII expression once daily for 3 days prior to the induction of ischemia. Transient cerebral ischemia (15 min) and reperfusion were induced by four-vessel occlusion in Sprague-Dawley rats as an animal model for transient cerebral I/R. The expression of related proteins was examined by immunoprecipitation and immunoblotting. Neuronal death in the rat hippocampus was detected by histology and histochemistry. The results indicate that CaMKII antisense ODNs inhibit several of the processes that are normally induced by cerebral I/R, including CaMKII expression, increased CaMKII?GluR6?PSD-95 signaling module assembly, GluR6 serine phosphorylation and JNK3 activation. Alternatively, CaMKII antisense ODNs also exhibit a significant neuroprotective role against cerebral I/R-induced cell death. These results provide the first evidence that CaMKII antisense ODNs can exert neuroprotective effects on cerebral I/R-induced cell death. The possible molecular mechanisms underlying this effect include 1) an inhibition of CaMKII expression and subsequent suppression of the assembly of the CaMKII?GluR6?PSD-95 signaling module, 2) GluR6 serine phosphorylation, and 3) reduced JNK3 activation.
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Purpose:The mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Or...
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Purpose:The mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Orai1). They were found to take a pivotal part in Ca<sup>2+</sup>-dependent procedures and involved in the development of central sensitization and pain. Ca<sup>2+</sup>/calmodulin-dependent protein kinase IIα (CaMKIIα), regulated by Ca<sup>2+</sup>/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKIIα.Materials and Methods:Intra-operative infusion of remifentanil (1.0 μg kg<sup>-1</sup> min<sup>-1</sup>, 60 min) was used to establish a RIPH rat model. The SOCCs blocker (YM-58483) was applied intrathecally to confirm the results. Animal behavioral tests including paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were performed at -24, 2, 6, 24, 48 h after incision and remifentanil treatments. The protein expression of STIM1, Orai1, CaMKIIα, and p-CaMKIIα was assayed with Western blot, and the number of STIM1 and Orai1 positive cells was shown by immunofluorescence.Results:Remifentanil administration significantly induced postoperative mechanical and thermal hyperalgesia, as well as increased STIM1 and Orai1 protein expression in the spinal dorsal horn. Furthermore, the intrathecal administration of YM-58483 effectively alleviated remifentanil-induced postoperative mechanical and thermal hyperalgesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKIIα but had no effect on the expression of STIM1 and Orai1.Conclusion:Our study demonstrated that SOCCs are involved in RIPH. The over-expressed STIM1 and Orai1 in the spinal cord contribute to RIPH via mediating the phosphorylation of CaMKIIα. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.? 2021 Zhou et al.
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Inflammation plays an important role in the development of cardiovascular diseases (CVDs), suggesting that the immune system is a target of therapeutic interventions used for treating CVDs. This study evaluated mechanisms underlyi...
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Inflammation plays an important role in the development of cardiovascular diseases (CVDs), suggesting that the immune system is a target of therapeutic interventions used for treating CVDs. This study evaluated mechanisms underlying inflammatory response and cardiomyocyte hypertrophy associated with bacterial lipopolysaccharide (LPS)- or heat shock protein 60 (HSP60)-induced Toll-like receptor (TLR) stimulation and the effect of a small interfering RNA (siRNA) against Ca2+/calmodulin-dependent kinase II delta B (CaMKIIδB) on these outcomes. Our results showed that treatment with HSP60 or LPS (TLR agonists) induced cardiomyocyte hypertrophy and complement system C3 and factor B gene expression. In vitro silencing of CaMKIIδB prevented complement gene transcription and cardiomyocyte hypertrophy associated with TLR 2/4 activation but did not prevent the increase in interleukin-6 and tumor necrosis factor-alfa gene expression in primary cultured cardiomyocytes. Moreover, CaMKIIδB silencing attenuated nuclear factor-kappa B expression. These findings supported the hypothesis that CaMKIIδB acts as a link between inflammation and cardiac hypertrophy. Furthermore, the present study is the first to show that extracellular HSP60 activated complement gene expression through CaMKIIδB. Our results indicated that a stress stimulus induced by LPS or HSP60 treatment promoted cardiomyocyte hypertrophy and initiated an inflammatory response through the complement system. However, CaMKIIδB silencing prevented the cardiomyocyte hypertrophy independent of inflammatory response induced by LPS or HSP60 treatment.
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we wish to draw the attention of your readership to an intriguingdevelopment in neurogenic hypertension that was reported in thelournal of Neuroscience late last year.1 while 1 in every 3 Americanadults now experience elevated blo...
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we wish to draw the attention of your readership to an intriguingdevelopment in neurogenic hypertension that was reported in thelournal of Neuroscience late last year.1 while 1 in every 3 Americanadults now experience elevated blood pressures, the majority presentwith primary hypertension,the pathology of which is incompletelyunderstood. It has been postulated that many cases of treatmentrefractory primary hypertension may be of a neurological origin 2 - i.e.sympathetically-driven increases in the vasoconstrictor tone ofresistance vessels, leading to elevated arterial blood pressure.
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Long-lasting synaptic changes following information acquisition are critical steps for memory. In this process, long-term potentiation (LTP) is widely considered as one of the major cellular mechanisms modifying synaptic strength....
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Long-lasting synaptic changes following information acquisition are critical steps for memory. In this process, long-term potentiation (LTP) is widely considered as one of the major cellular mechanisms modifying synaptic strength. It can be classified into early phase LTP (E-LTP) and late phase LTP (L-LTP) based on its duration. Using genetically modified mice, investigators have recognized the critical role of CaMKII in E-LTP and memory. However, its function in L-LTP, which is strongly dependent on gene transcription and protein synthesis, is still unclear. In this review, we discuss how different isoforms of CaMKII are coordinated to regulate gene expression in an activity-dependent manner, and thus contribute to L-LTP and memory. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. (C) 2015 Elsevier B.V. All rights reserved.
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This study investigated the role of calcium(2+)/calmodulin-dependent protein kinase II (CaMKII), a protein in the second messenger pathway of NMDA receptors, in the ventral tegmental area (VTA) in the acquisition and performance o...
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This study investigated the role of calcium(2+)/calmodulin-dependent protein kinase II (CaMKII), a protein in the second messenger pathway of NMDA receptors, in the ventral tegmental area (VTA) in the acquisition and performance of conditioned approach learning. Male Long-Evans rats (N = 79) were exposed to 3 (to test acquisition) or 7 (to test performance) conditioning sessions in which they received 30 paired presentations of a light stimulus (CS) and a food pellet (US) on a random time schedule. These conditioning sessions were then followed by one 30-min session without the CS or US and lastly by a CS-only test session, where only the light stimulus was presented (without food) according to the same schedule as the conditioning sessions. Bilateral intra-VTA injections of KN93 (vehicle, 3.0, 4.5 or 6.0 mu g/0.5 mu L), a CaMKII inhibitor, were administered prior to each conditioning session to test effects on the acquisition of conditioned approach or prior to the CS-only test session to test effects on the performance of conditioned approach. KN93, when given prior to conditioning sessions, significantly reduced the number of conditioned approach responses emitted during CS presentations in the CS-only test. When KN93 was given prior to the CS-only test it had no effect. These results suggest that CaMKII activation in the VTA is necessary for the acquisition, but not the performance, of reward-related learning.
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Vascular dementia (VD) is a common disease that occurs during human aging. Gastrodin (GAS) has potential benefits for the prevention and treatment of VD. In the present study, we investigated the effects of GAS on cognitive dysfun...
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Vascular dementia (VD) is a common disease that occurs during human aging. Gastrodin (GAS) has potential benefits for the prevention and treatment of VD. In the present study, we investigated the effects of GAS on cognitive dysfunction in rats with VD induced by permanent middle cerebral artery occlusion (pMCAO) and explored the underlying mechanism. Immunohistochemical and western blot analyses revealed that GAS attenuated hippocampal levels of LC3 (microtubule-associated protein 1 light chain 3), p62, and phosphorylated CaMKII (Ca2+-calmodulin stimulated protein kinase II) in VD rats. Additionally, our results revealed that cobalt chloride blocked autophagic flux in HT22 cells, which was confirmed by increased levels of LC3 and p62 when combined with chloroquine. Notably, GAS ameliorated the impaired autophagic flux. Furthermore, we confirmed that GAS combined with KN93 (a CaMKII inhibitor) or CaMKII knockdown did not impact the reduced p62 levels when compared with GAS treatment alone. Furthermore, a co-immunoprecipitation assay demonstrated that endogenous p62 bound to CaMKII, as confirmed by mass spectrometric analysis after the immunoprecipitation of p62 from HT22 cells. These findings revealed that GAS attenuated autophagic flux dysfunction by inhibiting the Ca2+/CaMKII signaling pathway to ameliorate cognitive impairment in VD.
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Vascular smooth muscle cells (VSMCs) help to maintain the normal physiological contractility of arterial vessels to control blood pressure; they can also contribute to vascular disease such as atherosclerosis. Ca2+/calmodulin-depe...
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Vascular smooth muscle cells (VSMCs) help to maintain the normal physiological contractility of arterial vessels to control blood pressure; they can also contribute to vascular disease such as atherosclerosis. Ca2+/calmodulin-dependent kinase II (CaMKII), a multifunctional enzyme with four isoforms and multiple alternative splice variants, contributes to numerous functions within VSMCs. The role of these isoforms has been widely studied across numerous tissue types; however, their functions are still largely unknown within the vasculature. Even more understudied is the role of the different splice variants of each isoform in such signaling pathways. This review evaluates the role of the different CaMKII splice variants in vascular pathological and physiological mechanisms, aiming to show the need for more research to highlight both the deleterious and protective functions of the various splice variants.
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