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MBC in Press, published online ahead of print December 20, 2006
Mol. Biol. Cell 10.1091/mbc.E06-10-0914

A more recent version of this article appeared on February 1, 2007
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Submitted on October 12, 2006
Revised on November 21, 2006
Accepted on November 30, 2006

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,*{dagger} Seiji Torii,* Hiromi Yokota-Hashimoto,* Koichi Okamoto,{dagger} Toshiyuki Takeuchi,* Hiroshi Gomi,* and Tetsuro Izumi*

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

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 using multiple effector proteins. However, the precise roles of these effector proteins in particular cell types largely remain uncharacterized, except for those in pancreatic {beta} cells and in melanocytes. Here we showed that one of the Rab27a/b effectors, exophilin4/Slp2-a, is specifically expressed in pancreatic {alpha} cells, in contrast to another effector, granuphilin, in {beta} 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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