ATP regulation of type 1 inositol 1,4,5-trisphosphate receptor channel gating by allosteric tuning of Ca2+ activation

Don On Daniel Mak, Sean McBride, J. Kevin Foskett

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Abstract

Inositol 1,4,5-trisphosphate (InsP3) mobilizes intracellular Ca2+ by binding to its receptor (InsP3R), an endoplasmic reticulum-localized Ca2+ release channel. Patch clamp electrophysiology of Xenopus oocyte nuclei was used to study the effects of cytoplasmic ATP concentration on the cytoplasmic Ca2+ ([Ca2+](i)) dependence of single type 1 InsP3R channels in native endoplasmic reticulum membrane. Cytoplasmic ATP free-acid ([ATP](i)), but not the MgATP complex, activated gating of the InsP3-liganded InsP3R, by stabilizing open channel state(s) and destabilizing the closed state(s). Activation was associated with a reduction of the half-maximal activating [Ca2+](i) from 500 ± 50 nM in 0 [ATP](i) to 29 ± 4 nM in 9.5 mM [ATP](i), with apparent ATP affinity = 0.27 ± 0.04 mM, similar to in vivo concentrations. In contrast, ATP was without effect on maximum open probability or the Hill coefficient for Ca2+ activation. Thus, ATP enhances gating of the InsP3R by allosteric regulation of the Ca2+ sensitivity of the Ca2+ activation sites of the channel. By regulating the Ca2+-induced Ca2+ release properties of the InsP3R, ATP may play an important role in shaping cytoplasmic Ca2+ signals, possibly linking cell metabolic state to important Ca2+-dependent processes.

Original languageEnglish (US)
Pages (from-to)22231-22237
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number32
DOIs
StatePublished - Aug 6 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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