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cAMP-GEFII is a direct target of cAMP in regulated exocytosis

Nature Cell Biology volume 2, pages 805–811 (2000)Cite this article

Abstract

Although cAMP is well known to regulate exocytosis in many secretory cells, its direct target in the exocytotic machinery is not known. Here we show that cAMP-GEFII, a cAMP sensor, binds to Rim (Rab3-interacting molecule, Rab3 being a small G protein) and to a new isoform, Rim2, both of which are putative regulators of fusion of vesicles to the plasma membrane. We also show that cAMP-GEFII, through its interaction with Rim2, mediates cAMP-induced, Ca2+-dependent secretion that is not blocked by an inhibitor of cAMP-dependent protein kinase (PKA). Accordingly, cAMP-GEFII is a direct target of cAMP in regulated exocytosis and is responsible for cAMP-dependent, PKA-independent exocytosis.

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Figure 1: Comparison of the structures of Rim2 and Rim1, and the interaction between Rab3A and Rim2.
Figure 2: Interaction of cAMP-GEFII, Rim and Rab3A, and the GEF activity of cAMP-GEFII.
Figure 3: Comparison of the distributions of cAMP-GEFII, Rim1 and Rim2 mRNA.
Figure 4: Effect of cAMP-GEFII on Ca2+-dependent secretion.
Figure 5: Effects of Rim2(ΔA) on the interaction of cAMP-GEFII and full-length Rim2 and on cAMP-GEFII-mediated exocytosis.
Figure 6: Effects of Rim2(ΔB) and syntenin on cAMP-GEFII-mediated exocytosis.
Figure 7: Model of cAMP-dependent exocytosis.

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Acknowledgements

We thank T. Sasaki for helpful advice and K. Yamaguchi for technical assistance. We also thank M. Takahashi for critical reading of the manuscript. This work was supported by a Grant-in-Aid for Creative Basic Research (10NP0201) from the Ministry of Education, Science, Sports and Culture; by Scientific Research Grants from the Ministry of Health and Welfare, Japan; by the Uehara Memorial Foundation; by a grant from Novo Nordisk Pharma Ltd.; by a grant for studies on the pathophysiology and complications of diabetes from Tsumura Pharma Ltd.; and by the Yamanouchi Foundation for Research on Metabolic Disorders. T.S. is supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

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Author notes

  1. Nobuaki Ozaki: On leave from the First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466-8550, Japan

  2. Nobuaki Ozaki and Tadao Shibasaki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan

    Nobuaki Ozaki, Tadao Shibasaki, Yasushige Kashima, Takashi Miki, Hiroaki Ueno, Yasuhiro Sunaga, Hideki Yano & Susumu Seino

  2. Department of Molecular Immunology, Core Research for Evolutional Science and Technology (CREST), Chiba University Graduate School of Medicine, Chiba, 260- 8670, Japan

    Kazuo Takahashi

  3. Department of Virology II, National Institute of Infectious Disease, Tokyo, 162-8640, Japan

    Yoshiharu Matsuura

  4. Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan

    Toshihiko Iwanaga

  5. Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, 565-0871, Japan

    Yoshimi Takai

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Correspondence to Susumu Seino.

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Ozaki, N., Shibasaki, T., Kashima, Y. et al. cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol 2, 805–811 (2000). https://doi.org/10.1038/35041046

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