Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

Coleman, S.K., Hou, Y., Willibald, M., Semenov, A., Moykkynen, T. and Keinänen, K. 2016. Aggregation Limits Surface Expression of Homomeric GluA3 Receptors. Journal of Biological Chemistry. 291, pp. 8784-8794. doi:10.1074/jbc.M115.689125

TitleAggregation Limits Surface Expression of Homomeric GluA3 Receptors
AuthorsColeman, S.K., Hou, Y., Willibald, M., Semenov, A., Moykkynen, T. and Keinänen, K.
Abstract

AMPA receptors are glutamate-gated
cation channels assembled from GluA1-4
subunits and have properties that are strongly
dependent on the subunit composition. The
subunits have different propensities to form
homomeric or various heteromeric receptors
expressed on cell surface, but the underlying
mechanisms are still poorly understood. Here,
we examined the biochemical basis for the poor
ability of GluA3 subunits to form homomeric
receptors, linked previously to two amino acid
residues, Y454 and R461, in its ligand-binding
domain (LBD). Surface expression of GluA3
was improved by co-assembly with GluA2 but
not with stargazin, a trafficking chaperone and
modulator of AMPA receptors. The secretion
efficiency of GluA2 and GluA3 LBDs paralleled
the transport difference between the respective
full-length receptors and was similarly
dependent on Y454/R461, but not on LBD
stability. In comparison to GluA2, GluA3
homomeric receptors showed a strong and
Y454/R461-dependent tendency to aggregate
both in the macroscopic scale measured as
lower solubility in nonionic detergent and in the
microscopic scale evident as the preponderance
of hydrodynamically large structures in
density gradient centrifugation and native gel
electrophoresis. We conclude that the impaired
surface expression of homomeric GluA3
receptors is caused by nonproductive assembly
and aggregation to which LBD residues Y454
and R461 strongly contribute. This aggregation inhibits the entry of newly synthesized GluA3
receptors to the secretory pathway.

KeywordsAMPA receptors, assembly, ionotropic glutamate receptors, protein aggregation, protein
Article numberjbc.M115.689125.
JournalJournal of Biological Chemistry
Journal citation291, pp. 8784-8794
ISSN1083-351X
Year2016
PublisherAmerican Society for Biochemistry and Molecular Biology
Accepted author manuscriptColeman et al_revised 2.pdf
Digital Object Identifier (DOI)doi:10.1074/jbc.M115.689125
Publication dates
Published24 Feb 2016

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