title: Functional significance of the kainate receptor GluR6(M836I) mutation that is linked to autism.
abstract: Previous studies revealed a linkage of the kainate receptor GluR6 with autism, a pervasive developmental disorder. Mutational screening in autistic patients disclosed the amino acid exchange M836I in a highly conserved domain of the cytoplasmic C-terminal region of GluR6. Here, we show that this mutation leads to GluR6 gain-of-function. By using the two-electrode voltage clamp technique we observed a significant increase of current amplitudes of mutant GluR6 compared to wild type GluR6. Western blotting of oocytes injected with mutant or wild type GluR6 cRNA and transfection of EGFP-tagged GluR6 receptors into COS-7 cells revealed an enhanced plasma membrane expression of GluR6(M836I) compared to wild type GluR6. Membrane expression of GluR6(M836I) but not of wild type GluR6 seems to be regulated by Rab11 as indicated by our finding that GluR6(M836I) but not wild type GluR6 showed increased current amplitudes and protein expression when coexpressed with Rab11. Furthermore, injection of GTP plus Rab11A protein into oocytes increased current amplitudes in GluR6(M836I) but not in wild type GluR6. By contrast, Rab5 downregulated the currents in oocytes expressing wild type GluR6 but had only little, statistically not significant effects on currents in oocytes expressing GluR6(M836I). Our data on altered functional properties of GluR6(M836I) provide a functional basis for the postulated linkage of GluR6 to autism. Furthermore, we identified new mechanisms determining the plasma membrane abundance of wild type GluR6 and GluR6(M836I).
authors.affiliation: Department of Physiology I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.forename: Ganna
authors.initials: G
authors.lastname: Korniychuk
authors.forename: Regina
authors.initials: R
authors.lastname: Schwarz
authors.forename: Ravshan
authors.initials: R
authors.lastname: Baltaev
authors.forename: Oana N
authors.initials: ON
authors.lastname: Ureche
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Mack
authors.forename: Zhan-Lu
authors.initials: ZL
authors.lastname: Ma
authors.forename: Michael
authors.initials: M
authors.lastname: Hollmann
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D009154:Mutation; D009865:Oocytes; D018408:Patch-Clamp Techniques; D018092:Kainic Acid Receptors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014982:Xenopus laevis; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor; D000099193:rab11 GTP-Binding Proteins
chemical_list: D018092:Kainic Acid Receptors; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000097806:GluK2 Kainate Receptor; D000099193:rab11 GTP-Binding Proteins