Kinesin-1 Regulates Extrasynaptic Targeting of NMDARs and Neuronal Vulnerability Toward Excitotoxicity

Abstract

Summary N-methyl-D-aspartate (NMDA) receptor (NMDAR) is highly compartmentalized in neurons, and its dysfunction has been implicated in various neuropsychiatric and neurodegenerative disorders. Recent failure to exploit NMDAR antagonization as a potential therapeutic target has driven the need to identify molecular mechanisms that regulate NMDAR compartmentalization. Here, we report that the reduction of Kif5b, the heavy chain of kinesin-1, protected neurons against NMDA-induced excitotoxicity and ischemia-provoked neurodegeneration. Direct binding of kinesin-1 to the GluN2B cytoplasmic tails regulated the levels of NMDAR at extrasynaptic sites and the subsequent influx of calcium mediated by extrasynaptic NMDAR by regulating the insertion of NMDARs into neuronal surface. Transient increase of Kif5b restored the surface levels of NMDAR and the decreased neuronal susceptibility to NMDA-induced excitotoxicity. The expression of Kif5b was repressed in cerebral ischemia preconditioning. Our findings reveal that kinesin-1 regulates extrasynaptic NMDAR targeting and signaling, and the reduction of kinesin-1 could be exploited to defer neurodegeneration.

Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain

“…Ischemic/hypoxic injury facilitates glutamate release and increased Ca ++ levels in the cytoplasm. Blocking NMDA receptors inhibits the inward flow of calcium ions and reduces neuronal injury (Lin et al, 2019). We previously demonstrated that MK801 reduced Glu-activated Ca ++ influx in neuronal cells expressing the Ca ++ probe gCaMP5 .…”

Understanding how kinesin motor proteins regulate postsynaptic function in neuron

“…Specific kinesins also directly control the endosomal transport of NMDA receptors. The surface expression of extrasynaptic NMDA receptor depends on KIF5B, which may involve endosomes [69]. In contrast, KIF21B affects the surface expression of synaptic NMDA receptor in recycling endosome by constraining the dynamics of Neurobeachin [28].…”

Kinesin Nanomotors Mediated Trafficking of NMDA-Loaded Cargo as A Novel Target in Chronic Pain

“…Evidence shows that inhibition of KIF5b expressions has resulted in reduced excitotoxicity induced by NMDA, hence exerting a neuroprotective effect. 54 Low levels of KIF5b inhibit calcium channels preventing Ca 2+ influx inside the neuron. To this pipeline, a study has reported the effect of various antineoplastic agents on kinesin-1 and rationalized its implication for neuropathy.…”

“…But a study has shown that, in peripheral nerve-injured rats, there was no change in expression of KIF5B in DRG . KIF5b has been revealed to regulate extra-synaptic NMDAR distribution and signaling. , The NR2B subunit of extra-synaptic NMDAR binds to the C terminus of the KIF5b tail. Evidence shows that inhibition of KIF5b expressions has resulted in reduced excitotoxicity induced by NMDA, hence exerting a neuroprotective effect .…”