CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors

Abstract

Calmodulin-dependent kinase II (CaMKII) is key for longterm potentiation of synaptic AMPA receptors. Whether CaMKII is involved in activity-dependent plasticity of other ionotropic glutamate receptors is unknown. We show that repeated pairing of pre-and postsynaptic stimulation at hippocampal mossy fibre synapses induces long-term depression of kainate receptor (KAR)-mediated responses, which depends on Ca 2 þ influx, activation of CaMKII, and on the GluK5 subunit of KARs. CaMKII phosphorylation of three residues in the C-terminal domain of GluK5 subunit markedly increases lateral mobility of KARs, possibly by decreasing the binding of GluK5 to PSD-95. CaMKII activation also promotes surface expression of KARs at extrasynaptic sites, but concomitantly decreases its synaptic content. Using a molecular replacement strategy, we demonstrate that the direct phosphorylation of GluK5 by CaMKII is necessary for KAR-LTD. We propose that CaMKII-dependent phosphorylation of GluK5 is responsible for synaptic depression by untrapping of KARs from the PSD and increased diffusion away from synaptic sites.

Exciting Times: New Advances Towards Understanding the Regulation and Roles of Kainate Receptors

“…LTD of KARs at MF-CA3 synapses is induced by a spike timing-, Ca 2+ influx-, and CaMKII-dependent plasticity mechanism, which is absent in slices from GluK5 −/− mice [87]. CaMKII phosphorylates the C-terminal domain of GluK5 in vitro and a phosphomimetic mutation enhances surface expression, but reduces synaptic localisation, in neurons.…”

“…However, whether this is due to direct binding of KARs to PSD95 and, if it is, which subunits are responsible, remains to be determined. Moreover, as discussed below, regulation of the interaction between GluK5 and PSD95 is required for long-term depression (LTD) of KARs at MF-CA3 synapses [87].…”

“…Postsynaptic KARs at MF-CA3 synapses undergo plastic changes, and exhibit several forms of LTD that can be induced by different stimulation protocols [15,87]. Chamberlain et al showed that SUMOylation of GluK2 is required for activity-dependent long-term depression of kainate receptor-mediated synaptic transmission (KAR LTD).…”

PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses

“…Further studies are needed to show the variation of the reduction of KARs among synapses, using focal uncaging experiments or quantitative immune-electron microscopic study of KAR subunits. Carta et al (2013) showed that phosphorylation of GluK5 by CaMKII diminished the binding between GluK5 and PSD-95, and extrasynaptic KARs were increased compensatory. Recently, it was also reported that KARs-mediated synaptic transmission was increased by overexpression of GluK4, and exogenous GluK4 is colocalized with endogenous PSD-95 at mossy fiber-CA3 synapses (Aller et al, 2015).…”

Heterologous Regulation of Mu-Opioid (MOP) Receptor Mobility in the Membrane of SH-SY5Y Cells

“…Also, the stimulation of NPFF receptors induces the recruitment f ␤-arrestin to the MOP receptor with a retention at the plasma membrane and no endocytosis, as observed by confocal imaging of fluorescence complementation between the MOP receptor and ␤-arrestin (19). Finally, as for glycine and kainate receptors where phosphorylation drives the dynamic exchange between synaptic and extrasynaptic location (72,73), such post-translational modifications could play a role in MOP receptor mobility changes. As described below, this probably occurs in the case of the MOP/NPFF receptor couple.…”