Biology Reference
In-Depth Information
Thus, CaMKII-dependent phosphorylation of SAP-97 regulates the association of SAP-97
with the PSD, providing a fine molecular mechanism responsible for the synaptic delivery of
SAP-97-interacting proteins, such as GluR1 and Kv4.2.
SynGAP is a ras GTPase-activating protein detected only in the brain (Chen et al., 1998).
It plays a crucial role in the early development of the brain and in the control of synaptic
plasticity in the adult brain (Komiyama et al., 2002). SynGAP has many sites of
phosphorylation by CaMKII, and is a good substrate of that kinase. Phosphorylation of
synGAP by CaMKII increases its Ras GTPase-activating activity by 70-95% (Oh et al.,
2004).
Neuronal nitric oxide synthase (nNOS) is phosphorylated by various protein kinases,
such as CaM kinases, PKA, and PKC (Bredt et al., 1992). nNOS activity is stimulated by
increases in Ca
2+
due to NMDA-receptor activation. CaMKII directly phosphorylates nNOS
at Ser-847, and the enzyme activity decreases 50-60% with suppression of CaM binding
(Hayashi et al., 1999).
Arc protein and mRNA expression is strongly induced by synaptic activation which
evokes LTP (Lyford et al., 1995). Arc may play a role in stabilizing activity-dependent
changes in synaptic efficacy. Arc protein is concentrated in the PSD, and is increased after
electroconvulsive treatment (Donai et al. 2003). In neuroblastoma cells expressing Arc and
CaMKII, Arc potentiates the action of CaMKII for neurite extension, suggesting that Arc and
CaMKII in the PSD play an important role in activity-induced synaptic modification (Donai
et al. 2003).
Protein synthesis-dependent late-phase LTP (L-LTP) in the hippocampus requires the
influx of Ca
2+
through NMDA receptor to activate CaMKII. CaMKII stimulates protein
synthesis in depolarized hippocampal neurons through phosphorylation of the mRNA
translation factor cytoplasmic polyadenylation element-binding protein (CPEB), and this
phosphorylation is rapidly reversed by PP1 (Atkins et al., 2005).
The regulation of many other PSD proteins by CaMKII is not well characterized, and
further studies would be required to understand the synaptic plasticity.
(6)
N
EURONAL
D
ISORDERS
R
ELATED TO A
D
YSFUNCTION OF
C
A
MKII
6-1. Alzheimer's disease
Alzheimer's disease (AD), a progressive neurodegerative disorder, is characterized by the
formation of neurofibrillary tangles (NFTs) and amyloid plaques. The tangles are composed
of straight and paired helical filaments (PHFs), with a major component being an aberrantly
hyperphosphorylated form of the microtuble-associated protein tau, normally expressed in
axons. Abnormal phosphorylation of tau is related to the formation of PHFs in the AD brain.
A number of protein kinases can phosphorylate tau (Lovestone & Reynolds, 1997). About
one-fourth of the phosphorylation sites as found in AD tau are phosphorylated by CaMKII,
suggesting that the kinase is involved in the abnormal phosphorylation of tau in AD brain
(Singh, et al. 1996; Yoshimura et al. 2003). Increased phosphorylation of tau alone does not
induce cell death in neuroblastoma cells overexpressing tau. Some additional stimuli may be
