Integration of ATP, cAMP, and Ca2+ Signals in Insulin Granule Exocytosis
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- 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}med.kobe-u.ac.jp
Abstract
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.
Footnotes
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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.
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- Accepted May 11, 2004.
- Received March 12, 2004.
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