Abstract
We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P2. In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P2 in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory.
Highlights
Excitatory neurotransmission has been thoroughly described at hippocampal synapses, especially those between Schaffer collaterals and dendrites of CA1 pyramidal neurons [1]
serum- and glucocorticoid-inducible kinase 3 (SGK3) mRNA is upregulated in hippocampus after NMDA receptor activation
As a first step to evaluate whether SGK3 plays a regulatory role in dynamic processes at the glutamatergic synapses, we determined the mRNA level of SGK3 in hippocampus after pharmacological NMDA receptor stimulation
Summary
Excitatory neurotransmission has been thoroughly described at hippocampal synapses, especially those between Schaffer collaterals and dendrites of CA1 pyramidal neurons [1]. Synaptic glutamate evokes an excitatory postsynaptic current (EPSC) that is mediated almost entirely by AMPA receptors. We here identify a novel mechanism involving NMDA receptor-triggered, SGK3-dependent stimulation of PIKfyve with subsequent formation of PI(3,5)P2, which modulates RAB11A-facilitated vesicle transport to the plasma membrane, leading to an increased abundance of GluA1 receptor subunits in the plasma membrane. We suggest that this novel mechanism plays a role in the dynamic regulation of GluA1 at synapses
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