Biology Reference
In-Depth Information
The presence and organization of the signaling machinery varies among different synaptic
types. This information is crucial because the complement of signaling complexes at a
synapse determines how it interacts and encodes information.
5-2-2. Translocation of CaMKII to the PSD
Recent studies have led to a model of the molecular steps of CaMKII's translocation and
activation that can explain its role in neuronal plasticity. Autophosphorylation-dependent
reversible translocation of α CaMKII to the PSD was demonstrated using an isolated PSD
and purified CaMKII (Strack et al., 1997; Yoshimura et al., 1997). The discovery may be the
initial step in elucidating this structural process and understanding the mechanism by which
CaMKII increases synaptic strength. When CaMKII is autophosphorylated in the presence of
Ca
2+
and calmodulin, the kinase associates with the PSD to form the PSD-CaMKII complex.
CaMKII is recruited to the NMDA receptor NR2B subunit through the cytoplasmic carboxyl-
terminal domain of the subunit. The CaMKII-NR2B complex maintains the kinase-activated
state (Bayer et al., 2001). After high-potassium treatment, the accumulation of CaMKII on the
cytoplasmic face is observed in cultured hippocampal neurons, concomitant with the
thickening of postsynaptic densities (Dosemeci et al. 2001). At the PSD, CaMKII associates
with the cyclin-dependent protein kinase 5 (CDK5) activators p35 and p39, and the
association is increased by the activation of the glutamate receptor (Dhavan et al., 2002).
CaMKII also binds to α actinin
via
p35/p39. Cross-talk between the cdk5 and CaMKII signal
transduction pathways may contribute to synaptic plasticity. CaMKII also interacts with
densin-180, forming ternary complex with α actinin at the PSD (Walikonis et al., 2001).
After its dephosphorylation by the actions of protein phosphatase 1(PP1), CaMKII is
released from the PSD (Yoshimura et al., 1999). The level of CaMKII in the PSD can affect
LTP and hippocampal-dependent learning. Thus, α CaMKII is a key player in the regulation
of plasticity.
5-2-3. Phosphorylation and regulation of PSD proteins by CaMKII
CaMKII substrates and interacting proteins
CaMKII of the PSD-CaMKII complex is active and has Ca
2+
-independent activity. It can
phosphorylate a large number of PSD proteins in both the presence and absence of Ca
2+
. Most
substrates have been identified by proteomic analysis (Yoshimura et al., 2000; Yoshimura et
al., 2002; Fink & Meyer, 2002; Yamauchi, 2002). Table 3 summarizes CaMKII substrates
and interacting proteins in the PSD fraction. The substrates include receptor and ion channel
proteins, scaffold and adaptor proteins, motor proteins, cytoskeletal proteins, enzymes, and
membrane proteins. Potential substrates are various glutamate receptors, synaptic GTPase
activating protein (SynGAP), and PSD-95/Disc-large/ZO-1 (PDZ) proteins including PSD-95
and SAP-97.The interacting proteins include sytoskeletal proteins, motor proteins, and
regulatory protein of protein kinases.
Regulation of receptors and ion channels in the PSD
The PSD contains various types of glutamate receptors, including NMDA receptors, α-
amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, and metabotropic
glutamate receptors (mGluR). These receptors are a substrate of CaMKII (Yoshimura et al.,
