From insulin synthesis to secretion: Alternative splicing of type 2 ryanodine receptor gene is essential for insulin secretion in pancreatic β cells

Hiroshi Okamoto, Shin Takasawa, Yasuhiko Yamamoto

Research output: Contribution to journalReview article

5 Citations (Scopus)

Abstract

Increases in the intracellular Ca2+ concentration in pancreatic islets, resulting from the Ca2+ mobilization from the intracellular source through the ryanodine receptor, are essential for insulin secretion by glucose. Cyclic ADP-ribose, a potent Ca2+ mobilizing second messenger synthesized from NAD+ by CD38, regulates the opening of ryanodine receptor. A novel ryanodine receptor mRNA (the islet-type ryanodine receptor) was found to be generated from the type 2 ryanodine receptor gene by the alternative splicing of exons 4 and 75. The islet-type ryanodine receptor mRNA is expressed in a variety of tissues such as pancreatic islets, cerebrum, cerebellum, and other neuro-endocrine cells, whereas the authentic type 2 ryanodine receptor mRNA (the heart-type ryanodine receptor) was found to be generated using GG/AG splicing of intron 75 and is expressed in the heart and the blood vessel. The islet-type ryanodine receptor caused a greater increase in the Ca2+ release by caffeine when expressed in HEK293 cells pre-treated with cyclic ADP-ribose, suggesting that the novel ryanodine receptor is an intracellular target for the CD38-cyclic ADP-ribose signal system in mammalian cells and that the tissue-specific alternative splicing of type 2 ryanodine receptor mRNA plays an important role in the functioning of the cyclic ADP-ribose-sensitive Ca2+ release.

Original languageEnglish
Pages (from-to)176-183
Number of pages8
JournalInternational Journal of Biochemistry and Cell Biology
Volume91
DOIs
Publication statusPublished - 2017 Oct

Keywords

  • Alternative splicing
  • Cyclic ADP-ribose
  • Poly(ADP-ribose) polymerase/synthetase
  • Ryanodine receptor
  • The OKAMOTO model

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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