Integration of ATP, cAMP, and Ca2+ Signals in Insulin Granule Exocytosis

  1. Tadao Shibasaki,
  2. Yasuhiro Sunaga and
  3. Susumu Seino
  1. Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
  1. Address correspondence and reprint requests to S. Seino, Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017. E-mail: seino{at}


Intracellular ATP, cAMP, and Ca2+ are major signals involved in the regulation of insulin secretion in the pancreatic β-cell. We recently found that the ATP-sensitive K+ channel (KATP channel) as an ATP sensor, cAMP-GEFII as a cAMP sensor, Piccolo as a Ca2+ sensor, and l-type voltage-dependent Ca2+ channel (VDCC) can interact with each other. In the present study, we examined the effects of cAMP and ATP on the interaction of cAMP-GEFII and sulfonylurea receptor-1 (SUR1). Interaction of cAMP-GEFII with SUR1 was inhibited by the cAMP analog 8-bromo-cAMP but not by ATP, and the inhibition by 8-bromo-cAMP persisted in the presence of ATP. In addition, SUR1, cAMP-GEFII, and Piccolo could form a complex. Piccolo also interacted with the α11.2 subunit of VDCC in a Ca2+-independent manner. These data suggest that the interactions of the KATP channel, cAMP-GEFII, Piccolo, and l-type VDCC are regulated by intracellular signals such as cAMP and Ca2+ and that the ATP, cAMP, and Ca2+ signals are integrated at a specialized region of pancreatic β-cells.


  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    [Ca2+]i, intracellular Ca2+ concentration; CAZ, cytoskeletal matrix associated with the active zone; Epac, exchange protein directly activated by cAMP; GEF, guanine nucleotide exchange factor; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GST, glutathione S-transferase; KATP channel, ATP-sensitive K+ channel; MBP, maltose-binding protein; NBF, nucleotide-binding fold; PKA, protein kinase A; SNAP, soluble N-ethylmaleimide-sensitive factor attachment protein; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SUR, sulfonylurea receptor; VAMP, vesicle-associated membrane protein; VDCC, voltage-dependent Ca2+ channel.

    • Accepted May 11, 2004.
    • Received March 12, 2004.
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