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.
Waites
Clarissa L
CL
Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, 1201 Welch Road, Palo Alto, CA 94304-5485, USA.
Specht
Christian G
CG
Härtel
Kai
K
Leal-Ortiz
Sergio
S
Genoux
David
D
Li
Dong
D
Drisdel
Renaldo C
RC
Jeyifous
Okun
O
Cheyne
Juliette E
JE
Green
William N
WN
Montgomery
Johanna M
JM
Garner
Craig C
CC
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