Cellular mechanisms that modulate kainate receptor trafficking and assembly

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Title: Cellular mechanisms that modulate kainate receptor trafficking and assembly
Author: Pornpun Vivithanaporn
Abstract: Kainate receptors (KARs ) in the mammalian brain play a variety of physiological roles that require selective assembly , intracellular trafficking , and synaptic targeting . Cytoplasmic and non -cytoplasmic determinants that modulate KAR expression at the plasma membrane have been recently characterized . The intracellular trafficking determinants are presumed to bind to chaperone proteins , but these proteins have not been identified for any KAR subunit . Here we identified two chaperone proteins that associated with the carboxy terminus but differently regulated the localization of KA2 receptors . We found that coatomer protein complex I (COPI ) subunits interacted with KA2 subunits at the arginine -based ER retention /retrieval motif and these associations were decreased in heteromeric GluR6a /KA2 receptors . Disruptions of COPI and KA2 associations by alanine mutations at the arginine -rich domain and elimination of COPI vesicles were correlated with the increased expression at the plasma membrane of KA2 receptors , indicating that COPI proteins regulated the ER localization of receptors . KA2 receptors also co -precipitated with three isoforms of 14 -3 -3 proteins ; only the KA2 and 14 -3 -3zeta association was correlated with higher plasma membrane expression of receptors . In addition to identifying cytoplasmic chaperone systems , we were interested in understanding the nature of a recently described trafficking checkpoint in non -cytoplasmic regions . Mutations in domains typically involved in glutamate binding and ion permeation disrupt expression of KARs at the plasma membrane . A conformational change of receptors after glutamate binding is proposed to permit egress of KARs from the ER . We mutated critical amino acid residues in the extracellular linker domain of GluR6a subunits and found that desensitization rates were only weakly correlated with plasma membrane expression levels . Alteration of these residues impaired other stages of receptor biosyntheis including assembly and degradation of mutated receptors . We found that mutations at the transduction linker collectively altered subunit assembly , degradation , desensitization and a post -assembly stage . Our characterizations of chaperone proteins and mechanisms that regulate intracellular trafficking provide a better understanding of cellular controls in the early stages of KAR biosynthesis .
URI: http : / /hdl .handle .net /2152 .3 /172
Date: 2007-06-08

Citation

Cellular mechanisms that modulate kainate receptor trafficking and assembly. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /172 .

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