Biology Reference
In-Depth Information
Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), a multifunctional Ser/Thr kinase
activated by Ca 2+ and calmodulin, is an evolutionally conserved protein. Ca 2+ is a universal
second messenger in eukaryotic cells. Cells typically maintain an intracellular Ca 2+ level of
10 -7 M, which is 10 4 times lower the level outside cells. The intracellular Ca 2+ level rapidly
increases up to 10 -4 M derived from extracellular and intracellular sources in response to extra
cellular stimuli. The predominant intracellular receptor of Ca 2+ is calmodulin, a EF-hand
family Ca 2+ -binding protein and highly conserved Ca 2+ sensor. Ca 2+ plays an essential role in
the basic operation of neurons through synaptic communication.
CaMKII is highly concentrated in the nervous system, and is specifically expressed
during the most active period in the formation of the synaptic network. CaMKII is one of the
major proteins in the postsynaptic density (PSD), which is an integral part of the postsynaptic
signaling machinery. This kinase has an extremely broad substrate specificity and
phosphorylates various kinds of proteins in the brain. Neuronal CaMKII is now recognized as
a critical mediator of neuronal plasticity that links transiently triggered Ca 2+ signals to
persistent changes in neuronal physiology. It regulates important neuronal functions, such as
neurotransmitter synthesis, neurotransmitter release, modulation of ion channel activity,
cellular transport, cell morphology and neurite extension, synaptic plasticity, learning and
memory, and gene expression. Because of these diverse functions, dysfunction of CaMKII
may cause neurological disorders.
The key role of CaMKII in synaptic plasticity and behavior makes it important to
understand its ability to achieve precise modulation of neuronal function. The basic
molecular mechanisms of CaMKII's functions, including in learning and memory, lie in its
interactions with and phosphorylation of putative modulatory targets. CaMKII is one of the
best candidates for a molecular component of the memory apparatus.
We will review the literature, with special focus on studies of the action of CaMKII in the
synapse, including both presynaptic terminals and postsynaptic regions. We also discuss that
dysfunction of CaMKII may cause neurological disorders. Several other reviews on CaMKII
provide additional perspectives for the interested reader (Hudmon & Schulman, 2002; Lisman
et al., 2002; Griffith et al., 2003; Colbran & Brown, 2004; Yamauchi, 2005).
(1) What is CaMKII
In the nearly 30 years since its discovery, CaMKII has been of major interest in the
region of brain science. There may be many new readers, however, who are not familiar with
CaMKII. We briefly describe the historical background and summarize the characteristics of
CaMKII. CaMKII was first identified in 1980 by gel filtration of Ca 2+ /calmodulin-dependent
protein kinases of rat brain by researchers monitoring the activation of tryptophan
hydroxylase and the phosphorylation of endogenous proteins in the brain (Yamauchi &
Fujisawa, 1980). It was the second peak eluted from a sizing column used to fractionate
Ca 2+ /calmodulin-dependent protein kinases from rat brain cytosol. The same kinase was
independently reported as calmodulin-dependent protein kinese that phosphorylates site II of
protein I (later named synapsin I) as a substrate (Kennedy & Greengard, 1981). Later, several
groups identified and purified the same kinase from various tissues and species (see review;
Hudmon & Schulamn, 2002; Yamauchi, 2005).
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