Regulation of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function by protein kinase C at serine-818 and threonine-840.
Three residues within the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluA1 C terminus (Ser818, Ser831, Thr840) can be phosphorylated by Ca(2+)/phospholipid-dependent protein kinase (PKC). Here, we show that PKC phosphorylation of GluA1 Ser818 or Thr840 enhances the weighted mean channel conductance without altering the response time course or agonist potency. These data support the idea that these residues constitute a hyper-regulatory domain for the AMPA receptor. Introduction of phosphomimetic mutations increases conductance only at these three sites within the proximal C terminus, consistent with a structural model with a flexible linker connecting the distal C-terminal domain to the more proximal domain containing a helix bracketed by Ser831 and Thr840. NMR spectra support this model and raise the possibility that phosphorylation can alter the configuration of this domain. Our findings provide insight into the structure and function of the C-terminal domain of GluA1, which controls AMPA receptor function and trafficking during synaptic plasticity in the central nervous system.
Department of Pharmacology (M.A.J., A.J., S.F.T.) and Department of Anesthesiology (A.J.), School of Medicine, and Department of Chemistry (G.W., J.P.S.), Emory University, Atlanta, Georgia; Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland (J.B., R.L.H.); and Department of Molecular Medicine, Cornell University, Ithaca, New York (R.E.O.).
Meagan A
MA
Jenkins
Gordon
G
Wells
Julia
J
Bachman
James P
JP
Snyder
Andrew
A
Jenkins
Richard L
RL
Huganir
Robert E
RE
Oswald
Stephen F
SF
Traynelis
D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D061251:Primary Cell Culture; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*
D011493:Protein Kinase C; D018091:Receptors, AMPA; D012694:Serine; D013912:Threonine