The local synthesis and degradation of proteins represent a particularly efficient means to adaptively modify the composition of targeted dendritic branches and associated synapses.
Recent data from our laboratory show that numerous mRNA encoding neurotransmitter receptors and voltage-gated channels are enriched in distal dendrites, indicating that local translation sustains local membrane protein turnover and may thus regulate dendritic excitability. In contrast to cytoplasmic proteins, local production of cell-surface proteins requires their processing by the secretory apparatus. Although the list of dendritic mRNAs encoding membrane and secreted proteins keeps growing, whether and how dendritically synthesized membrane proteins are locally processed by secretory organelles is still largely elusive.
Here we propose to assess the dendritic synthesis and turnover of key neurotransmitter receptors and voltage-gated channels controlling dendritic excitability by combining genetic engineering and biochemical approaches to selectively label and purify nascent proteins in specified dendritic compartments. Furthermore, by analyzing their glycosylation status and controlling the targeting of their mRNA to distal dendrites, we aim to understand how dendritically synthesized membrane proteins are processed by dendritic secretory organelles.
The turnover and glycosylation status of neuronal ion channels in vivo is largely unknown. By assessing a large cast of synaptic receptors and voltage-gated channels, this project will hopefully allow important inferences to be made about local protein synthesis, glycosylation and protein stability in brain. In the longer run, the proposed research will enable us to focus later functional studies on molecules displaying rapid turnover, and thus more likely to be acutely affected by adaptive regulations of secretory functions.
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