Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate

J Cell Biol. 2004 Jul 19;166(2):193-203. doi: 10.1083/jcb.200309146.

Abstract

Inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are channels responsible for calcium release from the endoplasmic reticulum (ER). We show that the anti-apoptotic protein Bcl-2 (either wild type or selectively localized to the ER) significantly inhibited InsP3-mediated calcium release and elevation of cytosolic calcium in WEHI7.2 T cells. This inhibition was due to an effect of Bcl-2 at the level of InsP3Rs because responses to both anti-CD3 antibody and a cell-permeant InsP3 ester were decreased. Bcl-2 inhibited the extent of calcium release from the ER of permeabilized WEHI7.2 cells, even at saturating concentrations of InsP3, without decreasing luminal calcium concentration. Furthermore, Bcl-2 reduced the open probability of purified InsP3Rs reconstituted into lipid bilayers. Bcl-2 and InsP3Rs were detected together in macromolecular complexes by coimmunoprecipitation and blue native gel electrophoresis. We suggest that this functional interaction of Bcl-2 with InsP3Rs inhibits InsP3R activation and thereby regulates InsP3-induced calcium release from the ER.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD3 Complex
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Calcium Channels / physiology*
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Inositol 1,4,5-Trisphosphate / pharmacology*
  • Inositol 1,4,5-Trisphosphate Receptors
  • Kinetics
  • Macromolecular Substances
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Transfection

Substances

  • CD3 Complex
  • Calcium Channels
  • ITPR1 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Macromolecular Substances
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Cytoplasmic and Nuclear
  • Inositol 1,4,5-Trisphosphate
  • Calcium