Subunit composition and alternative splicing regulate membrane delivery of kainate receptors.
Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors (GluRs) that play various roles in the regulation of synaptic transmission. The KAR subunits GluR5 and GluR6 exist under different splice variant isoforms in the C-terminal domain (GluR5a, GluR5b, GluR5c, GluR6a, GluR6b). The differential role of KAR subunit splice variants is presently unknown. In transfected COS-7 cells and neurons from wild-type and GluR5 x GluR6 mice, we have found that the subcellular localization and membrane delivery differed between these splice variants. GluR6a was highly expressed at the plasma membrane. GluR6b, GluR5a, and GluR5b were detected at lower levels in the plasma membrane and mainly colocalized with calreticulin in the endoplasmic reticulum (ER). GluR5c was strongly retained in the ER by an RXR motif. GluR6a acted as a key subunit splice variant promoting surface expression of ER-retained subunit splice variants when assembled in heteromeric KARs. Surface expression of GluR6a was independent of its PDZ (postsynaptic density-95/discs large/zona occludens-1) binding motif and was promoted by a stretch of four basic amino acid residues at its C terminus. Overall, splice variants and subunit composition of KARs regulate receptor trafficking from the endoplasmic reticulum to the plasma membrane.
Jaskolski
Frédéric
F
Laboratoire Physiologie Cellulaire de la Synapse, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5091, Institut François Magendie, Université Bordeaux 2, France.
Coussen
Françoise
F
Nagarajan
Naveen
N
Normand
Elisabeth
E
Rosenmund
Christian
C
Mulle
Christophe
C
D017398:Alternative Splicing / Q000235:genetics*; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097806:GluK2 Kainate Receptor
D046911:Macromolecular Substances; D020033:Protein Isoforms; D021122:Protein Subunits; D012333:RNA, Messenger; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor