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Vol. 18, Issue 2, 688-696, February 2007

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Exophilin4/Slp2-a Targets Glucagon Granules to the Plasma Membrane through Unique Ca²⁺-inhibitory Phospholipid-binding Activity of the C2A Domain

Miao Yu^*, Kazuo Kasai^*, Kazuaki Nagashima^*,, Seiji Torii^*, Hiromi Yokota-Hashimoto^*, Koichi Okamoto, Toshiyuki Takeuchi^*, Hiroshi Gomi^*, and Tetsuro Izumi^*

*Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan; and Department of Neurology, Gunma University School of Medicine, Maebashi 371-8511, Japan

Submitted October 12, 2006; Revised November 21, 2006; Accepted November 30, 2006
Monitoring Editor: Akihiko Nakano

Rab27a and Rab27b have recently been recognized to play versatile roles in regulating the exocytosis of secretory granules and lysosome-related organelles by using multiple effector proteins. However, the precise roles of these effector proteins in particular cell types largely remain uncharacterized, except for those in pancreatic cells and in melanocytes. Here, we showed that one of the Rab27a/b effectors, exophilin4/Slp2-a, is specifically expressed in pancreatic cells, in contrast to another effector, granuphilin, in cells. Like granuphilin toward insulin granules, exophilin4 promotes the targeting of glucagon granules to the plasma membrane. Although the interaction of granuphilin with syntaxin-1a is critical for the targeting activity, exophilin4 does this primarily through the affinity of its C2A domain toward the plasma membrane phospholipids phosphatidylserine and phosphatidylinositol-4,5-bisphosphate. Notably, the binding activity to phosphatidylserine is inhibited by a physiological range of the Ca²⁺ concentration attained after secretagogue stimulation, which presents a striking contrast to the Ca²⁺-stimulatory activity of the C2A domain of synaptotagmin I. Analyses of the mutant suggested that this novel Ca²⁺-inhibitory phospholipid-binding activity not only mediates docking but also modulates the subsequent fusion of the secretory granules.

Address correspondence to: Tetsuro Izumi (tizumi{at}showa.gunma-u.ac.jp)

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