Abstract
Author SummaryNeurons communicate with each other through specialized structures called synapses, and proper synapse function is fundamental for information processing and memory storage. The endosomal membrane trafficking pathway is crucial for the structure and function of synapses; however, the components of the neuronal endosomal transport machinery are poorly characterized. In this paper, we report that a protein called GRASP-1 is required for neurotransmitter receptor recycling through endosomes and back to the cell surface, as well as for the normal morphology of dendritic spines—the projections that form synapses—and for synaptic plasticity. We show that GRASP-1 coordinates coupling between early and later steps of the endocytic recycling pathway by binding to Rab4, a regulator of early endosomes, and to another endosomal protein found later in the pathway called syntaxin 13—a so-called SNARE protein involved in membrane fusion. GRASP-1 binds Rab4 with its N terminus and syntaxin 13 with its C terminus, suggesting that these interactions could structurally and functionally link early endosomes to those later in the recycling pathway. We propose a model in which GRASP-1 forms a molecular bridge between different endosomal membranes and the SNARE fusion machinery. Our study thus provides new mechanistic information about endosome function in neurons and highlights GRASP-1 as a key molecule that controls membrane receptor sorting and recycling during synaptic plasticity.
Highlights
In order to receive, process, and transmit information, neurons need substantially regulated mechanisms to locally redistribute membranes and proteins to synaptic sites
We report that a protein called glutamate receptor interacting protein (GRIP)-associated protein-1 (GRASP-1) is required for neurotransmitter receptor recycling through endosomes and back to the cell surface, as well as for the normal morphology of dendritic spines—the projections that form synapses—and for synaptic plasticity
We show that GRASP-1 coordinates coupling between early and later steps of the endocytic recycling pathway by binding to Rab4, a regulator of early endosomes, and to another endosomal protein found later in the pathway called syntaxin 13—a so-called SNARE protein involved in membrane fusion
Summary
Process, and transmit information, neurons need substantially regulated mechanisms to locally redistribute membranes and proteins to synaptic sites. Based on uptake of extracellular gold particles, visualization of clathrin assembly in living neurons and pre-embedding immunogold electron microscopy, it was shown that endosomal compartments are present in the dendritic shaft and spines and that endocytosis occurs at specialized endocytic zones lateral to the postsynaptic density (PSD) [1]. Using live-cell imaging and serial section electron microscopy, it was demonstrated that recycling endosomes are required for the growth and maintenance of dendritic spines [2]. Membrane recruitment from recycling endosomes is a common mechanism that cells employ to expand the plasma membrane and targets proteins in a polarized manner in such distinct processes as cytokinesis, cell-cell adhesion, phagocytosis, and cell fate determination [3,4]
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