Differential Modulation of Ca2+/Calmodulin-dependent Protein Kinase II Activity by Regulated Interactions with N-Methyl-D-aspartate Receptor NR2B Subunits and α-Actinin

Abstract

Postsynaptic roles of CaMKII␣ in synaptic plasticity are thought to require specific targeting to the postsynaptic density (PSD), a cytoskeletal structure juxtaposed to excitatory synapses that is enriched in neurotransmitter receptors and other signaling proteins. Immunohistochemical studies have revealed a wide range in the amount of CaMKII associated with individual PSDs (4, 5), consistent with a dynamic regulation of PSD targeting. Exogenous, Thr 286 -autophosphorylated CaMKII␣ ([P-T 286 ]CaMKII) binds specifically to isolated PSDs (6). Moreover, pharmacological treatments of hippocampal slices that activate CaMKII and induce long term potentiation, a form of synaptic plasticity, increase the amount of CaMKII associated with PSD-enriched subcellular fractions (6). Elegant studies of green fluorescent protein-CaMKII localization in cultured hippocampal neurons suggest that transient translocation of soluble CaMKII␣ to synapses in response to NMDA-type glutamate receptor (NMDAR) activation requires only Ca 2ϩ /calmodulin binding to CaMKII (7). However, mutagenesis studies indicate that Thr 286 autophosphorylation stabilizes the synaptic targeting of green fluorescent protein-CaMKII␣, whereas Thr 305/306 autophosphorylation promotes dissociation of synaptic green fluorescent protein-CaMKII␣ (8). Consistent with these data, the transgenic mouse knock-in mutation of Thr 305 in CaMKII␣ to Asp shows reduced CaMKII association with the PSD and changes in long term potentiation and learning and memory (2, 9, 10). Interestingly, a mouse model of Angelman mental retardation syndrome that has deficits in long term potentiation and spatial learning also displays decreased PSD-associated CaMKII␣ and increased autophosphorylation at Thr 305/306 (11). Other studies have shown that PKC activation can also drive synaptic translocation of CaMKII by a mechanism that is dependent on the actin cytoskeleton (12). In combination, these studies suggest that multiple, complex cellular mechanisms control PSD targeting of CaMKII. However, the molecular basis for these dynamic interactions is poorly defined.CaMKII binds several PSD-enriched CaMKII-associated proteins (CaMKAPs), including F-actin (13), cyclin-dependent protein kinase 5 (14), synGAP␤ (15), ␣-actinin (14, 16), densin-180 (16, 17), and multiple NMDAR subunits (18 -21

αCaMKII autophosphorylation levels differ depending on subcellular localization

“…In addition, T286 phosphorylation has been shown to decrease the dissociation rate of the kinase from the PSD (Shen et al, 2000;Bayer et al, 2006;Yoshimura and Yamauchi, 1997;Dosemeci et al, 2002). It has also been observed that autophosphorylation of T305/6 inhibits binding of αCaMKII to the PSD and several PSD proteins (Strack et al, 1997b;Leonard et al, 2002;Robison et al, 2005). Furthermore, it has been demonstrated that T305/6 phosphorylation increases the dissociation rate of the kinase from the PSD (Shen et al, 2000).…”

“…Like T286 phosphorylation, T305/6 phosphorylation has been shown to modulate protein-protein interactions of CaMKII. Phosphorylation of these residues inhibits kinase binding to isolated PSDs (Strack et al, 1997b), α-actinin (Robison et al, 2005), and the NMDAR subunits NR1 and NR2B (Leonard et al, 2002). In addition, T305/6 phosphorylation increases the dissociation rate of CaMKII from the PSD (Shen et al, 2000), and mimicking phosphorylation on these residues prevents while inhibiting phosphorylation enhances PSD association of the kinase (Elgersma et al, 2002).…”

CaMKII control of spine size and synaptic strength: Role of phosphorylation states and nonenzymatic action

“…Each subunit can bind several postsynaptic proteins (25,26), providing the possibility for the dodecamer holoenzyme to form a multimolecular complex. This binding is often facilitated by autophosphorylation at T286 but does not require subsequent enzymatic activity (26,27).…”

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

“…Thr-286 phosphorylation mildly enhances stimulated activity by 10 -20% (26), but also promotes additional Thr-305/ 306 phosphorylation that prevents subsequent Ca 2ϩ /CaM binding (26,31,32,38). By contrast, GluN2B binding actually reduces stimulated activity (10,39), but inhibits Thr-305/306 phosphorylation (10) (for review see Ref. 1).…”