Abstract
Kainate receptors (KARs) are mediators of excitatory neurotransmission in the mammalian central nervous system, and their efficient targeting and trafficking is critical for normal synaptic function. A key step in the delivery of KARs to the neuronal plasma membrane is the exit of newly assembled receptors from the endoplasmic reticulum (ER). Here we report the identification of a novel ER retention signal in the alternatively spliced C-terminal domain of the GluR5-2b subunit, which controls receptor trafficking in both heterologous cells and neurons. The ER retention motif consists of a critical arginine (Arg-896) and surrounding amino acids, disruption of which promotes ER exit and surface expression of the receptors, as well as altering their physiological properties. The Arg-896-mediated ER retention of GluR5 is regulated by a mutation that mimics phosphorylation of Thr-898, but not by PDZ interactions. Furthermore, two positively charged residues (Arg-900 and Lys-901) in the C terminus were also found to regulate ER export of the receptors. Taken together, our results identify novel trafficking signals in the C-terminal domain of GluR5-2b and demonstrate that alternative splicing is an important mechanism regulating KAR function.
Highlights
Kainate, NMDA,1 and AMPA receptors mediate glutamatergic excitatory neurotransmission in the mammalian central nervous system [1, 2]
We observed strong surface expression of the human interleukin-2 receptor ␣ subunit (Tac) and Tac-G5/2a (Fig. 1B), whereas Tac-G5/2b signal could not be detected on the plasma membrane, despite its robust intracellular expression (Fig. 1B)
This is consistent with previous studies demonstrating that Tac is synthesized as a 45-kDa immature form in the endoplasmic reticulum (ER) and further processed upon transport into the Golgi apparatus, resulting in a shift of molecular mass [13, 14]
Summary
NMDA,1 and AMPA receptors mediate glutamatergic excitatory neurotransmission in the mammalian central nervous system [1, 2]. We report the identification of a novel ER retention signal in the alternatively spliced C-terminal domain of the GluR5–2b subunit, which controls receptor trafficking in both heterologous cells and neurons. This signal consists of a critical Arg-896 and surrounding residues, disruption of which promotes ER exit and surface delivery of GluR5–2b receptors in both heterologous cells and hippocampal neurons.
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