Mechanism of Activity-Dependent Cargo Loading via the Phosphorylation of KIF3A by PKA and CaMKIIa

Neuron
Sotaro IchinoseNobutaka Hirokawa

Abstract

A regulated mechanism of cargo loading is crucial for intracellular transport. N-cadherin, a synaptic adhesion molecule that is critical for neuronal function, must be precisely transported to dendritic spines in response to synaptic activity and plasticity. However, the mechanism of activity-dependent cargo loading remains unclear. To elucidate this mechanism, we investigated the activity-dependent transport of N-cadherin via its transporter, KIF3A. First, by comparing KIF3A-bound cargo vesicles with unbound KIF3A, we identified critical KIF3A phosphorylation sites and specific kinases, PKA and CaMKIIa, using quantitative phosphoanalyses. Next, mutagenesis and kinase inhibitor experiments revealed that N-cadherin transport was enhanced via phosphorylation of the KIF3A C terminus, thereby increasing cargo-loading activity. Furthermore, N-cadherin transport was enhanced during homeostatic upregulation of synaptic strength, triggered by chronic inactivation by TTX. We propose the first model of activity-dependent cargo loading, in which phosphorylation of the KIF3A C terminus upregulates the loading and transport of N-cadherin in homeostatic synaptic plasticity.

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Citations

Jul 12, 2018·The Journal of Biological Chemistry·Sean M QuinnSusan P Gilbert
Sep 1, 2017·Nature Reviews. Neuroscience·Jeffrey J NirschlErika L F Holzbaur
Mar 21, 2020·Journal of Neurochemistry·Aleksandra TempesJacek Jaworski
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Apr 16, 2020·Molecular and Cellular Neurosciences·Megan R RadlerElias T Spiliotis
Apr 14, 2021·Developmental Biology·Courtney A BurgerMelanie A Samuel
Jul 22, 2021·The Journal of Cell Biology·Jessica J A Hummel, Casper C Hoogenraad
Sep 29, 2021·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Sara P AbrahamMichaela Bosakova
Nov 20, 2021·The FEBS Journal·Ruolin Fan, Kwok-On Lai

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