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Molecular and Cellular Biology, March 2002, p. 1714-1722, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1714-1722.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Ral-GTPase Influences the Regulation of the Readily Releasable Pool of Synaptic Vesicles

Atsuko Polzin,1,2 Michail Shipitsin,1 Takanori Goi,1 Larry A. Feig,1,2* and Timothy J. Turner2,3

Departments of Biochemistry,1 Neuroscience, Tufts University School of Medicine,2 Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 021113

Received 7 September 2001/ Returned for modification 25 October 2001/ Accepted 18 December 2001

The Ral proteins are members of the Ras superfamily of GTPases. Because they reside in synaptic vesicles, we used transgenic mice expressing a dominant inhibitory form of Ral to investigate the role of Ral in neurosecretion. Using a synaptosomal secretion assay, we found that while K+-evoked secretion of glutamate was normal, protein kinase C-mediated enhancement of glutamate secretion was suppressed in the mutant mice. Since protein kinase C effects on secretion have been shown to be due to enhancement of the size of the readily releasable pool of synaptic vesicles docked at the plasma membrane, we directly measured the refilling of this readily releasable pool of synaptic vesicles after Ca2+-triggered exocytosis. Refilling of the readily releasable pool was suppressed in synaptosomes from mice expressing dominant inhibitory Ral. Moreover, we found that protein kinase C and calcium-induced phosphorylation of proteins thought to influence synaptic vesicle function, such as MARCKS, synapsin, and SNAP-25, were all reduced in synaptosomes from these transgenic mice. Concomitant with these studies, we searched for new functions of Ral by detecting proteins that specifically bind to it in cells. Consistent with the phenotype of the transgenic mice described above, we found that active but not inactive RalA binds to the Sec6/8 (exocyst) complex, whose yeast counterpart is essential for targeting exocytic vesicles to specific docking sites on the plasma membrane. These findings demonstrate a role for Ral-GTPase signaling in the modulation of the readily releasable pool of synaptic vesicles and suggest the possible involvement of Ral-Sec6/8 (exocyst) binding in modulation of synaptic strength.

* Corresponding author. Mailing address: Departments of Biochemistry and Neuroscience, Tufts University School of Medicine, Boston, MA 02111. Phone: (617) 636-6956. Fax: (617) 636-2409. E-mail: larry.feig{at}tufts.edu.

Molecular and Cellular Biology, March 2002, p. 1714-1722, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1714-1722.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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