Rabphilin regulates SNARE-dependent re-priming of synaptic vesicles for fusion.
Synaptic vesicle fusion is catalyzed by assembly of synaptic SNARE complexes, and is regulated by the synaptic vesicle GTP-binding protein Rab3 that binds to RIM and to rabphilin. RIM is a known physiological regulator of fusion, but the role of rabphilin remains obscure. We now show that rabphilin regulates recovery of synaptic vesicles from use-dependent depression, probably by a direct interaction with the SNARE protein SNAP-25. Deletion of rabphilin dramatically accelerates recovery of depressed synaptic responses; this phenotype is rescued by viral expression of wild-type rabphilin, but not of mutant rabphilin lacking the second rabphilin C2 domain that binds to SNAP-25. Moreover, deletion of rabphilin also increases the size of synaptic responses in synapses lacking the vesicular SNARE protein synaptobrevin in which synaptic responses are severely depressed. Our data suggest that binding of rabphilin to SNAP-25 regulates exocytosis of synaptic vesicles after the readily releasable pool has either been physiologically exhausted by use-dependent depression, or has been artificially depleted by deletion of synaptobrevin.
Deák
Ferenc
F
Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Shin
Ok-Ho
OH
Tang
Jiong
J
Hanson
Phyllis
P
Ubach
Josep
J
Jahn
Reinhard
R
Rizo
Josep
J
Kavalali
Ege T
ET
Südhof
Thomas C
TC
D000818:Animals; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D013395:Sucrose / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020826:rab3A GTP-Binding Protein / Q000378:metabolism
D050683:R-SNARE Proteins; D050825:Synaptosomal-Associated Protein 25; D033921:Vesicular Transport Proteins; D013395:Sucrose; D020826:rab3A GTP-Binding Protein