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Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem

Nature volume 411, pages 701–706 (2001)Cite this article

Abstract

Voltage-dependent calcium (Ca2+) channels are involved in many specialized cellular functions1,2,3, and are controlled by intracellular signals such as heterotrimeric G-proteins4, protein kinases5,6 and calmodulin (CaM)7,8. However, the direct role of small G-proteins in the regulation of Ca2+ channels is unclear. We report here that the GTP-bound form of kir/Gem, identified originally as a Ras-related small G-protein that binds CaM9,10,11, inhibits high-voltage-activated Ca2+ channel activities by interacting directly with the β-subunit. The reduced channel activities are due to a decrease in α1-subunit expression at the plasma membrane. The binding of Ca2+/CaM to kir/Gem is required for this inhibitory effect by promoting the cytoplasmic localization of kir/Gem. Inhibition of L-type Ca2+ channels by kir/Gem prevents Ca2+-triggered exocytosis in hormone-secreting cells. We propose that the small G-protein kir/Gem, interacting with β-subunits, regulates Ca2+ channel expression at the cell surface.

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Figure 1: Characteristics of kir/Gem and its interaction with β-subunits.
Figure 2: Effects of kir/Gem on I–V relationships of Ca2+ channel currents in Xenopus oocytes and in BHK cells.
Figure 3: Subcellular localization of α11.2-subunits, wild-type kir/Gem and the W269G mutant.
Figure 4: Effects of wild-type (WT) kir/Gem and W269G mutant in hormone-secreting cells.
Figure 5: Model of regulation of Ca2+ channel expression at the cell surface by kir/Gem.

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Acknowledgements

We thank T. Tanabe and Y. Mori for rabbit α11.2 cDNA and BHK cell lines expressing Ca2+ channels, respectively; and Y. Takai for reading the manuscript. This work was supported by a Grant-in-Aid for Creative Basic Research from the Ministry of Education, Science, Sports and Culture Japan; by Scientific Research Grants from the Ministry of Health and Welfare, Japan; and by grants from Novo Nordisk Pharma, Japan; Yamanouchi Foundation for Research on Metabolic Disorders, Japan; and Swiss National Fund for Scientific Research. P.B. and K.N. are supported by Japan Society for the Promotion of Science Fellowships for Foreign Researchers and for Young Scientists, respectively.

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Author notes

  1. Pascal Béguin, Kazuaki Nagashima and Toshihiko Iwanaga: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan

    Pascal Béguin, Kazuaki Nagashima, Tadao Shibasaki, Yasushige Kashima, Nobuaki Ozaki & Susumu Seino

  2. Institut de Pharmacologie et de Toxicologie de l'Université de Lausanne, 27 rue du Bugnon, Lausanne, CH-1005, Switzerland

    Pascal Béguin & Käthi Geering

  3. Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, 1-8-1, Inohana, Chuo-ku, 260-8673, Chiba, Japan

    Tohru Gonoi

  4. Department of Molecular Immunology, Core Research for Evolutional Science and Technology (CREST), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan

    Kazuo Takahashi

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

    Toshihiko Iwanaga

Authors
  1. Pascal Béguin
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Correspondence to Susumu Seino.

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Béguin, P., Nagashima, K., Gonoi, T. et al. Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 411, 701–706 (2001). https://doi.org/10.1038/35079621

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