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A more recent version of this article appeared on June 1, 2002
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Submitted on September 25, 2001
Revised on February 1, 2002
Accepted on February 22, 2002
1 Institut de Biologie Cellulaire et de Morphologie, University of Lausanne, Switzerland
2 Laboratoire de Neurobiologie Cellulaire, Ecole Polytechnique Fédérale Lausanne, Switzerland
* Corresponding author. E-mail address: Romano.Regazzi{at}ibcm.unil.ch.
Granuphilin/Slp-4 is a member of the Synaptotagmin-like protein family expressed in pancreatic ß-cells and in pituitary gland. We show by confocal microscopy that both Granuphilin-a and -b colocalize with insulin-containing secretory granules positioned at the periphery of pancreatic ß-cells. Overexpression of Granuphilins in insulin-secreting cell lines caused a profound inhibition of stimulus-induced exocytosis. Granuphilins were found to bind to two components of the secretory machinery of pancreatic ß-cells, the small GTP-binding protein Rab3 and the SNARE-binding protein Munc-18. The interaction with Rab3 occurred only with the GTP-bound form of the protein and was prevented by a point mutation in the effector domain of the GTPase. Structure-function studies using Granuphilin-b mutants revealed that complete loss of Rab3 binding is associated with a reduction in the capacity to inhibit exocytosis. However, the Granuphilin/Rab3 complex alone is not sufficient to mediate the decrease of exocytosis, suggesting the existence of additional binding partners. Taken together, our observations indicate that Granuphilins play an important role in pancreatic ß-cell exocytosis. In view of the postulated role of Munc-18 in secretory vesicle docking, our data suggest that Granuphilins may also be involved in this process.
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