Shaping the Postsynaptic Landscape: Understanding the Role of Neuronal Activity in Local Secretory and Endocytic Protein Trafficking Dynamics

Released on by Ashley M. Bourke
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  • Shaping the Postsynaptic Landscape: Understanding the Role of Neuronal Activity in Local Secretory and Endocytic Protein Trafficking Dynamics Book Detail

  • Author : Ashley M. Bourke
  • Release Date : 2018
  • Publisher :
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  • Pages : 220
  • ISBN 13 :
  • File Size : 65,65 MB
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Shaping the Postsynaptic Landscape: Understanding the Role of Neuronal Activity in Local Secretory and Endocytic Protein Trafficking Dynamics by Ashley M. Bourke PDF Summary

Book Description: Neuronal development, morphology, excitability and synapse function rely on the ability to maintain and dynamically regulate the repertoire of channel, receptor and adhesion integral membrane proteins presented on the cell surface with extraordinary spatiotemporal specificity. The requirement for the exact spatiotemporal control of surface protein abundance and spatial distribution is an especially tall order for neuronal cells given their immense size, intricate morphology and segregated domain structure. Precise regulation of biosynthetic and endocytic protein trafficking is further confounded by synaptic activity, and the polarization of the somatic Golgi apparatus (GA) presents an arduous undertaking by newly synthesized dendritic integral membrane proteins. How are these challenges reconciled with space- and time-sensitive protein movements to effectively sustain neuronal function? Where, when and how key synaptic receptor proteins are trafficked to and within remote dendritic domains to meet the exigent demands of the cell have remained fundamental yet challenging questions in neuronal cell biology. Recent findings from the Kennedy lab and others propose the existence of a compartmentalized secretory trafficking network in dendrites yet experimentally investigating the relevance of local vs. centralized trafficking pathways has been impossible because currently there is no way to selectively control forward secretory trafficking from distinct subcellular domains. Here I describe the development and implementation of an opto/chemogenetic approach that allows for local, light-triggered forward trafficking of endoplasmic reticulum (ER)-sequestered proteins from user-defined regions within the cell (e.g. the neuronal cell body vs. individual dendritic branches). We discovered that proteins originating in the cell body could be transported deep into dendrites before surface insertion, with distinct cargoes displaying strikingly different kinetics, spatial distributions and activity dependencies. Surprisingly, proteins entering the dendritic secretory pathway were rapidly dispersed before reaching the surface. Additionally, we discovered that select cargoes are rapidly inserted in the plasma membrane at the axon initial segment (AIS), demonstrating a previously unappreciated role of the AIS as a major forward trafficking hub even for somatodendritic cargoes. Finally, we demonstrate that activity may have opposite effects on subcellular targeting of cargoes processed through somatic and dendritic networks. Our results provide the first quantitative characterization of compartmentalized secretory trafficking, placing important experimental constraints on current models for long-range and local protein trafficking. Once newly delivered synaptic proteins arrive at their functional destinations on the dendritic spine PM, their abundance and spatial distribution can be maintained or drastically modified through their endocytic trafficking depending on the current activity state of the synapse. We hypothesized that local alterations to synapses are mediated in part by regulated trafficking of postsynaptic proteins through organelles called recycling endosomes (REs), which act as reservoirs for important postsynaptic molecules. REs are housed within a large fraction of dendritic spines, the major postsynaptic sites of excitatory neurotransmission, and are thus well-poised to rapidly respond to changes in local activity to modulate synaptic structure and function. Using optical techniques coupled with local synapse activation and inactivation, we discovered that the rate of constitutive cargo flux through REs bidirectionally scales with synaptic activity at individual synaptic sites. Additionally, we demonstrate that RE cargo trafficking is coupled to synaptic activity by NMDA receptors and extracellular calcium. Finally, we demonstrate the synapse-specific, activity-dependent internalization of AMPA-type glutamate receptor 1 (GluA1), a key synaptic protein and known RE cargo. Overall, we have developed a novel optical approach for controlling secretory trafficking and we have characterized how neuronal activity influences the spatiotemporal properties of secretory and endocytic protein trafficking within distinct neuronal sub-compartments. These results provide crucial insight into how membrane trafficking processes might establish, maintain and modulate the molecular composition of synapses to support diverse forms of experience-dependent plasticity. Ongoing efforts are focused on both the proteomic mapping of the RE as well as the application of our novel optical approach to control the secretory trafficking of endogenous proteins.

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Protein Trafficking in Neurons

Protein Trafficking in Neurons

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The efficient delivery of cellular constituents to their proper location is of fundamental importance for all cells and is of particular interest to neuroscient