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The Journal of Neuroscience, July 15, 1999, 19(14):5834-5846
Rabphilin Knock-Out Mice Reveal That Rabphilin Is Not Required for Rab3 Function in Regulating Neurotransmitter Release
Oliver M. Schlüter1, 2, Eric Schnell3, Matthijs Verhage2, Thanos Tzonopoulos3, Roger A. Nicoll3, Roger Janz2, Robert C. Malenka3, Martin Geppert1, and Thomas C. Südhof2 1 Abteilung Molekulare Neurobiologie, Max-Planck-Institut für Experimentelle Medizin, 37075 Goettingen, Germany, 2 Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235, and 3 Departments of Psychiatry, Physiology, and Cellular and Molecular Pharmacology, The University of California, San Francisco, California 94143
Rab3A and rab3C 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 vesicles during exocytosis. Rabphilin contains two C2 domains, which could function as Ca2+ sensors in exocytosis and is phosphorylated as a function of stimulation. 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 rabphilin is mislocalized in rab3A knock-out mice, purified synaptic vesicles were shown to require rabphilin for binding of rab3A but not rab3A for binding of rabphilin. To test whether rabphilin is involved in localizing rab3s to synaptic vesicles and to explore the functions of rabphilin in regulating exocytosis, we have now analyzed knock-out mice for rabphilin. Mice that lack rabphilin are viable and fertile without obvious physiological impairments. In rabphilin-deficient mice, rab3A is targeted to synaptic vesicles normally, whereas in rab3A-deficient mice, rabphilin transport to synapses is impaired. These results show that rabphilin binds to vesicles via rab3s, consistent with an effector function of rabphilin for a synaptic rab3-signal. Surprisingly, however, no abnormalities in synaptic transmission or plasticity were observed in rabphilin-deficient mice; synaptic properties that are impaired in rab3A knock-out mice were unchanged in rabphilin knock-out mice. Our data thus demonstrate that rabphilin is endowed with the properties of a rab3 effector but is not essential for the regulatory functions of rab3 in synaptic transmission.
Key words: long-term potentiation; synaptic vesicles; exocytosis; mossy fiber terminals; C2 domain; Ca2+-binding proteins; rab3; synaptotagmin; protein kinase A
Copyright © 1999 Society for Neuroscience 0270-6474/99/19145834-13$05.00/0
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