Biology Reference
In-Depth Information
stimulation is enhanced by the selective protein kinase C (PKC) inhibitor, suggesting that the
proliferation and differentiation of neuronal cells are regulated by the activity of CaMKII and
PKC (Nomura et al., 1997). Autophosphorylation of Thr268 of α CaMKII is essential for this
kinase to exert cellular functions efficiently, as demonstrated using α CaMKII T268A or
T268D mutants (Goshima et al., 1993; Sogawa et al., 2000). The β-specific insertion of β
CaMKII is involved in the subcellular distribution of the kinase, and the subcellular
distribution is important in neurite extention (Urushihara & Yamauchi, 2001).
3-6. Toward a better understanding of molecular mechanisms
Remarkable progress has been made in understanding the role of CaMKII in various
types of synaptic plasticity and in learning and memory. CaMKII is activated during the
induction of LTP and this activation is necessary and sufficient for LTP. CaMKII also
increases synaptic strength. CaMKII is involved in LTP, LTD, hippocampus-dependent
learning, such as special learning, ocular dominance plasticity, seizure susceptibility, cued
and contextual conditioning, metaplasticity, and neurite extension. CaMKII is also involved
in protein synthesis and gene expression. These results indicate that careful regulation of the
kinase activity is required for the normal functioning of CaMKII.The key experiments have
been replicated in several laboratories and using independent methods.
Interest has been directed toward the molecular mechanism of these processes through
the action of this kinase. CaMKII's actions are related to the phosphorylation and/or
interaction of specific proteins. To understand the modulatory targets, and the impact that
CaMKII has on learning and memory at the cellular and systemic level, we describe the basic
molecular mechanisms of phosphorylation and binding interactions in the next sections.
(4)
P
RESYNAPTIC
P
ROTEINS
R
EGULATED
B
Y
C
A
MKII
CaMKII is involved in the regulation of neurotransmitter synthesis, neurotransmitter
secretion, and microtubule function in the presynapse. Although CaMKII targets various
kinds of proteins, CaMKII substrates and interacting proteins in the presynaptic terminal are
shown in Table 2.
4-1. Regulation of neurotransmitter synthesis
The nervous system makes use of two main classical substances for signaling: small-
molecule transmitters and neuroactive peptides. Neurotransmitters are contained in vesicles,
which release their contents
via
an exocytotic mechanism. Catecholamine and serotonin
transmitters are synthesized from the essential amino acids tyrosine and tryptophan,
respectively. The synthesis of catecholamines and serotonin is regulated by CaMKII through
phosphorylation of the rate-limiting enzymes of their biosynthesis, tyrosine hydroxylase (TH)
and tryptophan hydroxylase (TPH), respectively (Yamauchi, 2005). TH is phosphorylated by
CaMKII at Ser-19 (Itagaki et al., 1999), and TPH, at Ser-58 and Ser-260 (Jiang et al., 2000).
