Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate.
The synaptic insertion of GluR1-containing AMPA-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, mechanisms responsible for GluR1 insertion and retention at the synapse are unclear. The synapse-associated protein SAP97 directly binds GluR1 and participates in its forward trafficking from the Golgi network to the plasma membrane. Whether SAP97 also plays a role in scaffolding GluR1 at the postsynaptic membrane is controversial, attributable to its expression as a collection of alternatively spliced isoforms with ill-defined spatial and temporal distributions. In the present study, we have used live imaging and electrophysiology to demonstrate that two postsynaptic, N-terminal isoforms of SAP97 directly modulate the levels, dynamics, and function of synaptic GluR1-containing AMPARs. Specifically, the unique N-terminal domains confer distinct subsynaptic localizations onto SAP97, targeting the palmitoylated alpha-isoform to the postsynaptic density (PSD) and the L27 domain-containing beta-isoform primarily to non-PSD, perisynaptic regions. Consequently, alpha- and betaSAP97 differentially influence the subsynaptic localization and dynamics of AMPARs by creating binding sites for GluR1-containing receptors within their respective subdomains. These results indicate that N-terminal splicing of SAP97 can control synaptic strength by regulating the distribution of AMPARs and, hence, their responsiveness to presynaptically released glutamate.
Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, 1201 Welch Road, Palo Alto, CA 94304-5485, USA.
Clarissa L
CL
Waites
Christian G
CG
Specht
Kai
K
Härtel
Sergio
S
Leal-Ortiz
David
D
Genoux
Dong
D
Li
Renaldo C
RC
Drisdel
Okun
O
Jeyifous
Juliette E
JE
Cheyne
William N
WN
Green
Johanna M
JM
Montgomery
Craig C
CC
Garner
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017729:Presynaptic Terminals / Q000737:chemistry / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C501119:Dlg1 protein, rat; D008565:Membrane Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D018091:Receptors, AMPA; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid