Biology Reference
In-Depth Information
2002).Glutamate receptors are also phosphorylated by various kinds of protein kinases,
including PKC, cAMP-dependent protein kinase (PKA), and fyn tyrosin kinase, and regulated
by phosphorylation (Yamauchi, 2002). The AMPA receptor GluR1 subunit contains a single
phosphorylation site, Ser831, that when phosphorylated by CaMKII, enhances channel
function (Barria et al., 1997a). Biochemical studies have shown that receptor phosphorylation
occurs during LTP, as its induction promotes the incorporation of 32P into the GluR1 subunit
by CaMKII (Barria et al., 1997b). The phosphorylation of Ser831 alters the induction of LTP
which would be expected to increase the AMPA channel's conductance, and this has been
directly observed (Benke et al., 1998). In rat hippocampal neurons, LTP or increased activity
of CaMKII induces delivery of tagged AMPA receptors into synapses (Hayashi et al., 2000).
This effect is blocked by mutating a PDZ domain interaction site, indicating that trafficking
of AMPA receptors to synapses by CaMKII requires the association between the AMPA
receptor and a PDZ domain protein.
The NMDA receptor NR2B subunit is phosphorylated at Ser1303 by CaMKII (Omkumar
et al., 1996). α CaMKII enhances the extent and/or rate of desensitization of NMDA-induced
macroscopic currents in HEK293 cells co-expressing NR2B with the NR1 subunit, without
significantly changing other current parameters.This suggests a mechanism for the Ca
2+
-
dependent negative-feedback regulation of NMDA receptors (Sessoms-Sikes et al., 2005).
CaMKII also binds to the NMDA receptor NR2A subunit C-terminal domain with high
affinity. PKC-dependent phosphorylation at Ser-1416 of the NR2A C-terminal tail decreases
its affinity for α CaMKII, and promotes the dissociation of the α CaMKII
-
NR2A complex,
indicating that binding of CaMKII to the PSD is affected by PKC (Gardoni et al., 2001a &
2001b).
Members of the
Shaker
Kv channel family are localized to pre- and postsynaptic
components, and possible targets for phosphorylation by CaMKII. Kv1.4, a rapidly
inactivating Kv channel, is demonstrated to be phosphorylated and inactivated by CaMKII
(Roeper et al., 1997). CaMKII phosphorylates an amino-terminal residue, Ser123. This
phosphate is dephosphorylated by calcineurin (phosphatase 2B).The Ca
2+
-sensitive
phosphorylation/dephosphorylation of Kv1.4 has profound functional consequences for the
inactivation.
Regulation of PSD proteins phosphorylated by CaMKII
Many scaffold proteins, including PSD-95, are good substrates for CaMKII. CaMKII-
dependent phosphorylation of PSD-95 causes dissociation of NR2A from PSD-95, suggesting
that PSD-95 regulates the signaling transduction pathway downstream of the NMDA receptor
(Gardoni et al. 2006). Synaptic trafficking of synapse-associated protein 97 (SAP-97) is
modulated by CaMKII in cultured hippocampal neurons. Activation of CaMKII promotes the
recruitment of SAP-97 into dendritic spines (Mauceri et al., 2004). SAP-97 is involved in the
correct delivery and clustering of glutamate ionotropic receptors and K
+
channel proteins to
the PSD. CaMKII-dependent phosphorylation of SAP-97-Ser-39 caused a redistribution of
the AMPA receptor GluR1 subunit (Mauceri et al., 2004). SAP-97 also interacts Kv4.2, and
phosphorylation of SAP-97 by CaMKII regulates the subcellular localization of Kv4.2
(Gardoni et al. 2007). Kv4.2 is the pore-forming α subunit of the A-type K
+
channel and
critically involved in the regulation of dendritic excitability and plasticity. Kv4.2 is enriched
in the PSD fraction and specifically interacts with SAP-97
via
the PDZ domain of SAP-97.
