Critical regions for activation gating of the inositol 1,4,5-trisphosphate receptor

Keiko Uchida, Hiroshi Miyauchi, Teiichi Furuichi, Takayuki Michikawa, Katsuhiko Mikoshiba

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

To understand the molecular mechanism of ligand-induced gating of the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)/Ca2+ release channel, we analyzed the channel properties of deletion mutants retaining both the IP3-binding and channel-forming domains of IP3R1. Using intrinsically IP3R-deficient cells as the host cells for receptor expression, we determined that six of the mutants, those lacking residues 1-223, 651-1130, 1267-2110, 1845-2042, 1845-2216, and 2610-2748, did not exhibit any measurable Ca2+ release activity, whereas the mutants lacking residues 1131-1379 and 2736-2749 retained the activity. Limited trypsin digestion showed that not only the IP3-gated Ca2+-permeable mutants lacking residues 1131-1379 and 2736-2749, but also two nonfunctional mutants lacking residues 1-223 and 651-1130, retained the normal folding structure of at least the C-terminal channel-forming domain. These results indicate that two regions of IP3R1, viz. residues 1-223 and 651-1130, are critical for IP3-induced gating. We also identified a highly conserved cysteine residue at position 2613, which is located within the C-terminal tail, as being essential for channel opening. Based on these results, we propose a novel five-domain structure model in which both N-terminal and internal coupling domains transduce ligand-binding signals to the C-terminal tail, which acts as a gatekeeper that triggers opening of the activation gate of IP3R1 following IP3 binding.

Original languageEnglish
Pages (from-to)16551-16560
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number19
DOIs
Publication statusPublished - 2003 May 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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