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Neuronal Ca2+/calmodulin-dependent protein kinase II - Discovery, progress in a quarter of a century, and perspective: Implication for learning and memory

Department of Biochemistry, Graduate School of Pharmaceutical Sciences, University of Tokushima, Shomachi 1, Tokushima 770-8585, Japan.
Biological & Pharmaceutical Bulletin (Impact Factor: 1.78). 09/2005; 28(8):1342-54. DOI: 10.1248/bpb.28.1342
Source: PubMed

ABSTRACT Much has been learned about the activity-dependent synaptic modifications that are thought to underlie memory storage, but the mechanism by which these modifications are stored remains unclear. A good candidate for the storage mechanism is Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). CaM kinase II is one of the most prominent protein kinases, present in essentially every tissue but most concentrated in brain. Although it has been about a quarter of a century since the finding, CaM kinase II has been of the major interest in the region of brain science. It plays a multifunctional role in many intracellular events, and the expression of the enzyme is carefully regulated in brain regions and during brain development. Neuronal CaM kinase II regulates important neuronal functions, including neurotransmitter synthesis, neurotransmitter release, modulation of ion channel activity, cellular transport, cell morphology and neurite extension, synaptic plasticity, learning and memory, and gene expression. Studies concerning this kinase have provided insight into the molecular basis of nerve functions, especially learning and memory, and indicate one direction for studies in the field of neuroscience. This review presents the molecular structure, properties and functions of CaM kinase II, as a major component of neurons, based mainly developed on findings made in our laboratory.

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    • "Calmodulin trapping allows CaMKII to remain activated long after the initial Ca 2þ signal has dissipated, suggesting that CaMKII is a memory molecule crucial for LTP [4] [5]. Consistent with this notion, CaMKII-null mice present with impaired memory formation, and CaMKII is essential for genesis and maintenance of LTP in postsynaptic neurons [2]. Following presynaptic stimulation, CaMKII is activated in postsynaptic neurons, which creates a physiological imprint of the initial Ca 2þ signal, and increases translocation of NMDA receptors to the plasma membrane [6]. "
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    ABSTRACT: Ca2+/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in calcium pulses as a form of “metabolic memory”, just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of ß-cells to intervals of high glucose, followed by a 24-hour consolidation period to eliminate any acute metabolic effects. Strikingly, ß-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. Metabolic memory was reflected on the protein level by increased expression of proteins involved in glucose sensing and Ca2+-dependent vesicle secretion, and by elevated levels of the key ß-cell transcription factor MAFA. In summary, like neurons, human and mouse ß-cells are able to acquire and retrieve information.
    07/2014; 3(4). DOI:10.1016/j.molmet.2014.03.011
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    • "The p38 MAPK pathway has been implicated in numerous inflammatory diseases including atherosclerosis, rheumatoid arthritis, Alzheimer disease, and inflammatory bowel disease (Sweeney and Firestein 2004; Johnson and Bailey 2003). CaMKII, a serine/threonine-specific protein kinase regulated by the Ca 2? /calmodulin complex (Yamauchi 2005), is involved in a variety of signaling cascades and necessary for Ca 2? homeostasis and reuptake in cardiomyocytes (Anderson 2005). BiP, a glucose-regulated protein (GRP-78) or heat shock 70-kDa protein 5 (HSPA5), is a molecular chaperone located in the lumen of the ER that binds newly synthesized proteins as they are translocated into the ER, and maintains them in a state competent for subsequent folding and oligomerization (Ting and Lee 1988). "
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    ABSTRACT: As an effort to alleviate stent-induced cardiovascular injury including restenosis and thrombosis, advanced drug-eluting stent (ADES) with a bilayer construct composed of a top-coat made of collagen and a base-coat incorporated with N-nitrosomelatonin (NOMela)-loaded PLGA nanoparticles has been developed. NOMela is a hydrophobic prodrug of nitric oxide (NO) that is an endogenous anti-platelet compound. ADES was coated with PLGA nanoparticles via either electrophoretic deposition (EPD) technique or dip-coating technique, and their coating characteristics and efficacies were compared. The drug-loading efficacy and in vitro drug-release profiles from ADES were expressed with various variables including the additives to the collagen layer, the number of layers of the collagen top-coat, the hydrophobicity/hydrophilicity of the loaded drug, the coating technique of nanoparticles, and the concentration of coating emulsions in the EPD method. The morphological status of cross-section and surface of ADES was evaluated by laser scanning confocal microscope and scanning electronic microscope. The real-time release profiles of NO were assessed using the NO-microbiosensor. The anti-platelet activity of ADES was evaluated on the rabbit whole blood using an aggregometer. The intima formation and protein expression in aorta were examined using an in vivo rat model. Both collagen and PLGA used in ADES are biodegradable polymers that fully degrade and consequently produce less inflammation responses. NO released from ADES significantly reduced platelet aggregation in the rabbit blood as compared with those exposed to the control stents. ADES coated with a double layer consisted of collagen and PLGA and containing NOMela was less antigenic at the implanted sites and alleviating intima formation and thrombosis. An external exposure of aorta to NO elicits distinct and specific effects on mitogen-activated protein kinase (MAPK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) activities which evoke the endoplasmic reticulum (ER) stress response. These findings elucidated that coordinate and reciprocal alterations in the protein kinases followed by the ER stress protein expression are an integral feature of the in-stent-mediated cardiovascular injury.
    Journal of Nanoparticle Research 10/2013; 15(10). DOI:10.1007/s11051-013-1962-1 · 2.28 Impact Factor
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    • "In line with this, we found parallel decreases in the levels of three Ca 2 þ /calmodulin-dependent protein kinase subunits (CAMK2A, CAMK2B, and CAMK2D) in the frontal cortex from the PCP-injected rats analyzed in this study. The CAMK family regulates a range of processes associated with synaptic plasticity and cognition, including long-term potentiation (Fink and Meyer, 2002; Yamauchi, 2005), and has been associated previously with SCZ (Novak et al, 2006) and PCP treatment (Mouri et al, 2007b). We also found that subunits of the multifunctional calcium-dependent serine/ threonine phosphatase calcineurin A were altered in the PCP rats. "
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    ABSTRACT: Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic- and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca(2+) signaling (Ca(2+)/calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca(2+) regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ.Neuropsychopharmacology advance online publication, 14 August 2013; doi:10.1038/npp.2013.160.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2013; DOI:10.1038/npp.2013.160 · 7.83 Impact Factor
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