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J. Biol. Chem., Vol. 269, Issue 45, 27987-27991, Nov, 1994

Rab3A effector domain peptides induce insulin exocytosis via a specific interaction with a cytosolic protein doublet

S Olszewski, JT Deeney, GT Schuppin, KP Williams, BE Corkey and CJ Rhodes
E. P. Joslin Research Laboratory, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, Massachusetts 02215.

A key protein involved in the regulated exocytotic mechanism in neuroendocrine cells is the GTP-binding protein, Rab3A. Rab3A is thought to mediate exocytosis by an interaction of its effector domain with a putative effector protein. We demonstrate here that Rab3A effector domain peptides specifically stimulated insulin exocytosis in electroporated insulin-secreting cells (K0.5 activation, 6-8 microM) in a Ca(2+)-independent manner, although in the presence of Ca2+ insulin exocytosis was further potentiated. By using a 125I-radiolabeled photoactivated cross-linking Rab3A effector domain peptide, we identified a cytosolic protein doublet (REEP-1 and REEP-2), which specifically interacted with the Rab3A effector domain. Competitive inhibition studies revealed this protein-protein interaction to be at a concentration equivalent to that required for Rab3A effector domain peptides to trigger insulin exocytosis (Ki, 6-8 microM). Furthermore, under basal secretory conditions REEP-1 and -2 were membrane- associated, but upon stimulation of exocytosis they were released into a cytosolic fraction. Our results suggest that REEP-1 and -2 are part of the regulated exocytotic machinery, and their dissociation upon stimulation of hormone release (likely from a protein complex) may be essential to the mechanism that triggers regulated exocytosis in pancreatic beta-cells.
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