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• W1489247720 abstract "Thousands of intra- and extracellular processes define the identity of a neuron at a given time. These processes require an interplay between different molecules, including the communication of the plasmamembrane with intracellular vesicle compartments. For instance, synaptic formation requires intra- and extracellular processes for the formation of precise molecular attachments between pre- and postsynaptic neurons. Motor proteins such as kinesins, dyneins, and myosins are highly involved in regulating intracellular turnover and synaptic formation in neurons. Kinesins mainly transport cargos toward anterograde direction along microtubules and have been implicated in the delivery of material to synapses. Despite many studies which have discovered several different transport mechanisms, the transport mechanisms for specific cargos still remain elusive.Here, I report that gephyrin and GRIP1 (glutamate receptor-interacting protein 1) act as adaptor proteins which steer their respective cargos through different mechanisms. A gephyrin-mediated transport complex and a GRIP1-mediated transport complex, both of which use the same motor protein, KIF5, were investigated through two separate projects. The first project focuses on posttranslational modifications of microtubules and their impact on anterograde transport of a GlyR-gephyrin-KIF5 complex. In this project, I show that increasing neuronal activity through the application of 1 μM strychnine up-regulates polyglutamylation of tubulins, which interferes with ability of the gephyrin-mediated transport complex to be targeted into neurites. After depleting polyglutamylation of tubulins by infecting cells with Lentivirus carrying shRNA-PGs1, distribution of the complex is recovered. These results indicate that changes in neuronal activity alter cellular function by a crosstalk with intracellular transport of synaptic cargo into neurites. The second project focuses on a novel transport complex, N-Cadherin-GluR2-GRIP1-KIF5. Several recent studies have proposed that N-Cadherin, a Ca2+-dependent cell adhesion molecule, regulates synapse formation in mammalian central neurons. Independently, GRIP1 was previously shown to act as an adaptor protein for transporting GluR2-containing AMPA receptors driven by KIF5 motor proteins. Here, I show that N-Cadherin is also transported by KIF5 together with GRIP1. Expression of a dominant-negative KIF5C polypeptide, characterized by the deletion of its motor domain, caused N-Cadherin aggregation in the cell body and significantly interfered with N-Cadherin transport into neurites. Furthermore, competitive interference with N-Cadherin/GRIP1 binding or depolymerization of microtubules decreased N-Cadherin surface membrane levels upon heterologous expression. Therefore, N-Cadherin, similar as reported for the GluR2-containing AMPA receptor, is driven by a GRIP1-KIF5 transport complex. Consequently, I investigated whether both N-Cadherin and the GluR2-containing AMPA receptor are co-transported by the same adaptor-motor protein complex in neurons. Co-immunoprecipitation and co-localization experiments pointed to a complex consisting of N-Cadherin, GluR2-containing AMPA receptor, GRIP1, and KIF5. In line with these observation, electron microscopy detected N-Cadherin and the GluR2-containing AMPA receptor to share the same intracellular vesicles. Finally, I observed the co-transport of both proteins in neurites of living neurons by applying time-lapse video microscopy. These results suggest that N-Cadherin is transported together with a GluR2-GRIP1-KIF5 complex in the same vesicle. To my knowledge, this is the first report that describes co-transport of a cell adhesion molecule together with neurotransmitter receptors, both of which are known to be essential for the identity of excitatory spine synapses. As a result, I expect the findings from my two projects to extend the current understanding of somata to synapse targeting." @default.
• W1489247720 created "2016-06-24" @default.
• W1489247720 creator A5015351108 @default.
• W1489247720 date "2011-11-02" @default.
• W1489247720 modified "2023-09-27" @default.
• W1489247720 title "Analysis of the adaptor proteins, gephyrin and GRIP1, in KIF5-driven neuronal transport in Mus musculus, (Linnaeus, 1758)" @default.
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