Ca2+ influx through the NMDA receptor and subsequent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are crucial for learning and one of its physiological correlates, long-term potentiation (LTP). Ca2+/calmodulin promotes CaMKII binding to several postsynaptic proteins, including the NMDA receptor. These interactions strategically place CaMKII at locations where Ca2+ influx through the NMDA receptor is highest for further activation of CaMKII and for phosphorylation of nearby AMPA receptors and of other proteins that are important for LTP. Ca2+-dependent postsynaptic CaMKII clustering is of specific interest because LTP is synapse specific: only synapses that experience LTP-inducing high-frequency activity exhibit LTP. Ca2+-driven protein binding ensures that CaMKII accumulates only at those synapses undergoing LTP. This selectivity is economical and could contribute to the synapse specificity of LTP because downstream effects of CaMKII will occur mainly at synapses that accumulate CaMKII. In this article, we provide an overview of recent progress in postsynaptic CaMKII anchoring and discuss its implication in synaptic plasticity and the etiology and potential treatments of neurological diseases.
"Presynaptic effects of CaMKIIa on D3 receptors Liu et al. (2009) concluded that CaMKIIa regulates postsynaptic D3R in the NAc because they found the receptors at a very high density in the purified postsynaptic density. Evidence showing that CaMKIIa interacts with postsynaptic target proteins is abundant (Gardoni et al., 1998; Leonard et al., 1999; Strack et al., 1997; Merrill et al., 2005; Colbran and Brown, 2004; Bayer et al., 2006). Our experiments demonstrate that D3/CaMKIIa interactions modulate presynaptic function because they inhibit Ca 2þ -dependent depolarization-induced [ 3 H]GABA release. "
"Further characterization of proteins, which interact with the GluN1 subunit revealed several protein kinases; namely, calcium-calmodulin-dependent kinase II (subunits alpha, beta and delta) and serine/threonine protein kinase PAK1. Calcium-calmodulin-dependent kinase II (subunits alpha, beta and delta), is known to translocate to NMDA receptors in an activity-dependent manner (Bayer et al. 2001, 2006; Merrill et al. 2005) and the significance of this finding is probably initiating receptor trafficking, assembly and activation. "
[Show abstract][Hide abstract] ABSTRACT: Reduced daily intake of magnesium (Mg(2+)) is suggested to contribute to depression. Indeed, preclinical studies show dietary magnesium restriction (MgR) elicits enhanced depression-like behaviour establishing a causal relationship. Amongst other mechanisms, Mg(2+) gates the activity of N-methyl-D-asparte (NMDA) receptors; however, it is not known whether reduced dietary Mg(2+) intake can indeed affect brain NMDA receptor complexes. Thus, the aim of the current study was to reveal whether MgR induces changes in brain NMDA receptor subunit composition that would indicate altered NMDA receptor regulation. The results revealed that enhanced depression-like behaviour elicited by MgR was associated with reduced amygdala-hypothalamic protein levels of GluN1-containing NMDA complexes. No change in GluN1 mRNA levels was observed indicating posttranslational changes were induced by dietary Mg(2+) restriction. To reveal possible protein interaction partners, GluN1 immunoprecipitation and proximity ligation assays were carried out revealing the expected GluN1 subunit association with GluN2A, GluN2B, but also novel interactions with GluA1, GluA2 in addition to known downstream signalling proteins. Chronic paroxetine treatment in MgR mice normalized enhanced depression-like behaviour, but did not alter protein levels of GluN1-containing NMDA receptors, indicating targets downstream of the NMDA receptor. Collectively, present data demonstrate that dietary MgR alters brain levels of GluN1-containing NMDA receptor complexes, containing GluN2A, GluN2B, AMPA receptors GluA1, GluA2 and several protein kinases. These data indicate that the modulation of dietary Mg(2+) intake may alter the function and signalling of this receptor complex indicating its involvement in the enhanced depression-like behaviour elicited by MgR.
Brain Structure and Function 05/2014; 220(4). DOI:10.1007/s00429-014-0779-8 · 5.62 Impact Factor
"Given that a typical PSD has 80 CaMKII dodecamers/0.1 mm 2 (Chen et al., 2005), which translates into up to 240 dodecamers in larger PSDs (Feng et al., 2011), but has only at most 10–20 GluN2B-containing NMDARs (Feng et al., 2011), it appears likely that CaMKII is anchored not only via GluN2B but also other binding sites. Additional sites that require CaMKII activation via Ca 2+ /CaM or T286 autophosphorylation for binding are present on GluN1 (aa 845–861) and another site within the membrane proximal half of the C terminus of GluN2B (aa 839–1,120) (Leonard et al., 2002; Merrill et al., 2005). Densin is also part of the PSD (Walikonis et al., 2000) and a-actinin can associate with the PSD via binding to densin and NMDAR subunits (Walikonis et al., 2001; Wyszynski et al., 1997), constituting additional CaMKII attachment sites. "
[Show abstract][Hide abstract] ABSTRACT: While CaMKII has long been known to be essential for synaptic plasticity and learning, recent work points to new dimensions of CaMKII function in the nervous system, revealing that CaMKII also plays an important role in synaptic organization. Ca(2+)-triggered autophosphorylation of CaMKII not only provides molecular memory by prolonging CaMKII activity during long-term plasticity (LTP) and learning but also represents a mechanism for autoactivation of CaMKII's multifaceted protein-docking functions. New details are also emerging about the distinct roles of CaMKIIα and CaMKIIβ in synaptic homeostasis, further illustrating the multilayered and complex nature of CaMKII's involvement in synaptic regulation. Here, I review novel molecular and functional insight into how CaMKII supports synaptic function.
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