Stabilization of Ca2+-permeable AMPA receptors at perisynaptic sites by GluR1-S845 phosphorylation.
AMPA receptor (AMPAR) channel properties and function are regulated by its subunit composition and phosphorylation. Certain types of neural activity can recruit Ca(2+)-permeable (CP) AMPARs, such as GluR1 homomers, to synapses likely via lateral diffusion from extrasynaptic sites. Here we show that GluR1-S845 phosphorylation can alter the subunit composition of perisynaptic AMPARs by providing stability to GluR1 homomers. Using mice specifically lacking phosphorylation of the GluR1-S845 site (GluR1-S845A mutants), we demonstrate that this site is necessary for maintaining CP-AMPARs. Specifically, in the GluR1-S845A mutants, CP-AMPARs were absent from perisynaptic locations mainly due to lysosomal degradation. This regulation was mimicked by acute desphosphorylation of the GluR1-S845 site in wild-type mice by NMDA application. Furthermore, long-term depression (LTD) was associated with a reduction in perisynaptic CP-AMPAR levels. Our findings suggest that GluR1-S845 is necessary for maintaining CP-AMPARs on the surface, especially at perisynaptic sites, and suggest that the regulation of these receptors is involved in synaptic plasticity.
He
Kaiwen
K
Department of Biology, College of Chemical and Life Sciences and Neuroscience and Cognitive Science (NACS) Program, University of Maryland, College Park, MD 20742, USA.
Song
Lihua
L
Cummings
Laurel W
LW
Goldman
Jonathan
J
Huganir
Richard L
RL
Lee
Hey-Kyoung
HK
D015763:2-Amino-5-phosphonovalerate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D009154:Mutation; D009473:Neuronal Plasticity / Q000502:physiology; D018733:Nicotinic Antagonists / Q000378:metabolism; D010766:Phosphorylation; D011073:Polyamines / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D015763:2-Amino-5-phosphonovalerate; D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D011073:Polyamines; D021122:Protein Subunits; D018091:Receptors, AMPA; D012694:Serine; C034092:delta-philanthotoxin