Rabphilin knock-out mice reveal that rabphilin is not required for Rab3 function in regulating neurotransmitter release

Rab3A and rab3G are GTP-binding proteins of synaptic vesicles that regulate vesicle exocytosis. Rabphilin is a candidate rab3 effector at the synapse because it binds to rab3s in a GTP-dependent manner it is co-localized with rab3s on synaptic vesicles, and it dissociates with rab3s from the vesicle s during exocytosis. Rabphilin contains two C-2 domains, which could functi on as Ca2+ sensors in exocytosis and is phosphorylated as a function of sti mulation. However, it is unknown what essential function, if any, rabphilin performs. One controversial question regards the respective roles of rab3s and rabphilin in localizing each other to synaptic vesicles: although rabp hilin is mislocalized in rab3A knock-out mice, purified synaptic vesicles w ere shown to require rabphilin for binding of rab3A but not rab3A for bindi ng of rabphilin. To test whether rabphilin is involved in localizing rab3s to synaptic vesicles and to explore the functions of rabphilin in regulatin g exocytosis, we have now analyzed knock-out mice for rabphilin. Mice that lack rabphilin are viable and fertile without obvious physiological impairm ents. In rabphilin-deficient mice, rab3A is targeted to synaptic vesicles n ormally whereas in rab3A-deficient mice, rabphilin transport to synapses is impaired. These results show that rabphilin binds to vesicles via rab3s, c onsistent with an effector function of rabphilin for a synaptic rab3-signal . Surprisingly, however, no abnormalities in synaptic transmission or plast icity were observed in rabphilin-deficient mice; synaptic properties that a re impaired in rab3A knock-out mice were unchanged in rabphilin knock-out m ice. Our data thus demonstrate that rabphilin is endowed with the propertie s of a rab3 effector but is not essential for the regulatory functions of r ab3 in synaptic transmission.