TARP modulation of synaptic AMPA receptor trafficking and gating depends on multiple intracellular domains.
Previous work has established stargazin and its related family of transmembrane AMPA receptor regulatory proteins (TARPs) as auxiliary subunits of AMPA receptors (AMPARs) that control synaptic strength both by targeting AMPARs to synapses through an intracellular PDZ-binding motif and by modulating their gating through an extracellular domain. However, TARPs gamma-2 and gamma-8 differentially regulate the synaptic targeting of AMPARs, despite having identical PDZ-binding motifs. Here, we investigate the structural elements that contribute to this functional difference between TARP subtypes by using domain transplantation and truncation. We identify a component of synaptic AMPAR trafficking that is independent of the TARP C-terminal PDZ-binding motif, and we establish previously uncharacterized roles for the TARP intracellular N terminus, loop, and C terminus in modulating both the trafficking and gating of synaptic AMPARs.
Milstein
Aaron D
AD
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
Nicoll
Roger A
RA
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018091:Receptors, AMPA / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000378:metabolism*
C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D008565:Membrane Proteins; D018091:Receptors, AMPA; C515550:TARP gamma-8 protein, mouse