JNK activity modulates postsynaptic scaffold protein SAP102 and kainate receptor dynamics in dendritic spines

Abstract

We show here that the dynamics of the synaptic scaffold molecule SAP102 are negatively regulated by JNK inhibition, that SAP102 is a direct phosphorylation target of JNK3, and that SAP102 regulation by JNK is restricted to neurons that harbour mature synapses. We further demonstrate that SAP102 and JNK3 cooperate in the regulated trafficking of kainate receptors to the cell membrane. Specifically, we observe that SAP102, JNK3, and the kainate receptor subunit GluK2 exhibit overlapping expression at synaptic sites, and that modulating JNK activity influences the surface expression of the kainate receptor subunit GluK2 in a neuronal context. We also show that SAP102 participates in this process in a JNK-dependent fashion. In summary, our data support a model in which JNK-mediated regulation of SAP102 influences the dynamic trafficking of kainate receptors to postsynaptic sites, and thus shed light on common pathophysiological mechanisms underlying the cognitive developmental defects associated with diverse mutations.

Synapse-associated protein 102 – a highly mobile MAGUK predominate in early synaptogenesis

“…Furthermore, phosphorylation of the Ser632 (rat SAP102) in the I2 domain by casein kinase II (CK2) increases the synaptic enrichment of SAP102 while also decreasing its mobility in dendritic spines ( Wei et al, 2018 ). Similarly, Ser368 of SAP102 (human) can be phosphorylated by the c-Jun N-terminal kinases (JNKs) to affect the dynamics of SAP102, and this modification by JNK is restricted to neurons that harbor mature synapses ( Kunde et al, 2021 ). These results suggest that phosphorylation plays a key role in regulating SAP102 synaptic targeting and mobility.…”

“…Similarly, Ser368 of SAP102 (human) can be phosphorylated by the c-Jun N-terminal kinases (JNKs) to affect the dynamics of SAP102, and this modification by JNK is restricted to neurons that harbor mature synapses (Kunde et al, 2021). These results suggest that phosphorylation plays a key role in regulating SAP102 synaptic targeting and mobility.…”