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© The Rockefeller University Press, 0022-1295/1998//243/ $5.00
Journal of General Physiology, Volume 111, Number 2, 1998

Article

Rabphilin-3A: A Multifunctional Regulator of Synaptic Vesicle Traffic

M.E. Burns*,{ddagger}, T. Sasaki§, Y. Takai§, and G.J. Augustine*,{ddagger}

From the * Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710; {ddagger} Marine Biological Laboratory, Woods Hole, Massachusetts 02543; and § Department of Molecular Biology and Biochemistry, Osaka University Medical School, Osaka 565, Japan

We have investigated the function of the synaptic vesicle protein Rabphilin-3A in neurotransmitter release at the squid giant synapse. Presynaptic microinjection of recombinant Rabphilin-3A reversibly inhibited the exocytotic release of neurotransmitter. Injection of fragments of Rabphilin-3A indicate that at least two distinct regions of the protein inhibit neurotransmitter release: the NH2-terminal region that binds Rab3A and is phosphorylated by protein kinases and the two C2 domains that interact with calcium, phospholipid, and β-adducin. Each of the inhibitory fragments and the full-length protein had separate effects on presynaptic morphology, suggesting that individual domains were inhibiting a subset of the reactions in which the full-length protein participates. In addition to inhibiting exocytosis, constructs containing the NH2 terminus of Rabphilin-3A also perturbed the endocytotic pathway, as indicated by changes in the membrane areas of endosomes, coated vesicles, and the plasma membrane. These results indicate that Rabphilin-3A regulates synaptic vesicle traffic and appears to do so at distinct stages of both the exocytotic and endocytotic pathways.

Key Words: endocytosis • exocytosis • GTP-binding proteins • rabs • neurotransmitter release

Address correspondence to G.J. Augustine, Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, NC 27710. Fax: 919-684-4431; E-mail: georgea{at}neuro.duke.edu.

Abbreviations: PSP, postsynaptic potential


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