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: 1.83). 09/2005; 28(8):1342-54. DOI: 10.1248/bpb.28.1342
Source: PubMed


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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    • "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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    • "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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