Amisyn regulates exocytosis and fusion pore stability by both syntaxin-dependent and syntaxin-independent mechanisms

doi:10.1074/jbc.M505858200

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A more recent version of this article appeared on September 9, 2005 Originally published In Press as doi:10.1074/jbc.M505858200 on July 20, 2005

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Papers In Press, published online ahead of print July 22, 2005
J. Biol. Chem, 10.1074/jbc.M505858200
Submitted on May 31, 2005
Revised on July 20, 2005
Accepted on July 20, 2005

Amisyn regulates exocytosis and fusion pore stability by both syntaxin-dependent and syntaxin-independent mechanisms

John R. L. Constable, Margaret E. Graham, Alan Morgan, and Robert D. Burgoyne

The Physiological Laboratory, University of Liverpool, Liverpool L69 3BX

Corresponding Author: burgoyne{at}liv.ac.uk

Amisyn and tomosyn are related by the possession of a C-terminal VAMP-like domain that allows them to bind to syntaxin 1 and assemble into SNARE complexes. The formation of inactive complexes may sequester syntaxin and allow tomosyn and amisyn to act as inhibitors of exocytosis. We aimed to use adrenal chromaffin and PC12 cells to probe this possible mode of action of amisyn and tomosyn in dense core granule exocytosis. While tomosyn is expressed by adrenal chromaffin and PC12 cells, amisyn expression could not be detected allowing examination of the effect of introduction of amisyn expression onto a neuronal-like background. Overexpression of m-tomosyn1 and expression of amisyn both inhibited Ca2+-induced exocytosis in transfected PC12 cells. Surprisingly, this inhibition was not removed when amisyn and tomosyn constructs were used in which key residues required for efficient binding to syntaxin1 were mutated. The effect of amisyn was further characterised using carbon fibre amperometry in chromaffin cells. Expression of amisyn had no effect on the basic characteristics of the amperometric spikes but reduced the number of spikes elicited. This inhibitory action on the extent of exocytosis was also seen with the amisyn mutant deficient in syntaxin1-binding. In addition, expression of amisyn resulted in an increase in the life-time of the pre-spike foot and this effect was abolished by the mutations. These results show that tomosyn and amisyn can negatively regulate exocytosis independently of syntaxin and also that amisyn can regulate the stability of the fusion pore.

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