Biology Reference
In-Depth Information
Gear-shaped model of α CaMKII was also reported using three-dimensional electron
microscopy (Kolodziej et al. 2000)
.
Table 1 summarizes the characteristics of the CaMKII
molecule.
(2)
M
OLECULAR
P
ROPERTIES OF
C
A
MKII
AS A
M
EMORY
M
OLECULE
The interest in CaMKII has been fueled by its fascinating regulatory properties, which are
based on autophosphorylation, distribution, developmental change, and translocation. Based
on these properties, CaMKII is recognized as a memory molecule.
2-1. Autophosphorylation: Activation and inactivation of the kinase activity
Autophosphorylation provides critical regulation of CaMKII, both activation and
inactivation.
CaMKII is completely inactive in the absence of Ca
2+
and calmodulin, since the
autoinhibitory domain, present in the regulatory domain, blocks the active site of the kinase.
The autoinhibitory domain is disrupted by the binding of calmodulin at its C-terminal end,
which leads to de-inhibition of the kinase. The autoinhibitory domain can be further disrupted
by autophosphorylation of a key threonine residue common to all isoforms (Thr286 and
Thr287 of the α and β isoforms, respectively) (Fong et al., 1989; Hanson et al., 1989). This
phosphorylation converts the kinase to a Ca
2+
-independent enzyme. Autophosphorylation
increases the affinity of the kinase for calmodulin several hundred fold by reducing the
dissociation rate (Meyer et al., 1992). The Ca
2+
-independent activity of the enzyme prolongs
the Ca
2+
action transiently increased in response to nerve stimuli, and is involved
in long-term
potentiation (LTP), a basic process of learning and memory. Thus, CaMKII is postulated to
act as a “molecular switch” (Lisman, 1994).
Autophosphorylation of Thr305 and Thr306, inhibitory autophosphorylation sites, on
α and β CaMKII, respectively, occurs after phosphorylation at Thr286 (α) or Thr287 (β) in a
Ca
2+
-independent manner (Colbran & Soderling, 1990). This is responsible for the loss of
ability of CaMKII to bind Ca
2+
/calmodulin, resulting in a reduction of the kinase activity and
the association of CaMKII with PSD.
CaMKII activity is regulated bidirectionally, activation and inactivation, by the
autophosphorylation.
2-2. Distribution: Spatial and temporal expression of CaMKII in the brain
2-2-1. Immunocytochemistry
Immunoreactivity to CaMKII is present in neurons throughout the brain. CaMKII
composes up to 1% of total protein in the forebrain and 2% of that in the hippocampus
(Erondu & Kennedy, 1985). The ratio of α to β isoforms is about 3 : 1 and 1 : 4 in the adult
forebrain and cerebellum, respectively (McGuinness et al., 1985; Miller & Kennedy, 1985).
