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Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.

Proapoptotic BCL-2 family members BAX and BAK are required for the initiation of mitochondrial dysfunction during apoptosis and for maintaining the endoplasmic reticulum (ER) Ca(2+) stores necessary for Ca(2+)-dependent cell death. Conversely, antiapoptotic BCL-2 has been shown to decrease Ca(2+) concentration in the ER. We found that Bax(-/-)Bak(-/-) double-knockout (DKO) cells have reduced resting ER Ca(2+) levels because of increased Ca(2+) leak and an increase in the Ca(2+)-permeable, hyperphosphorylated state of the inositol trisphosphate receptor type 1 (IP3R-1). The ER Ca(2+) defect of DKO cells is rescued by RNA interference reduction of IP3R-1, supporting the argument that this channel regulates the increased Ca(2+) leak in these cells. BCL-2 and IP3R-1 physically interact at the ER, and their binding is increased in the absence of BAX and BAK. Moreover, knocking down BCL-2 decreases IP3R-1 phosphorylation and ER Ca(2+) leak rate in the DKO cells. These findings support a model in which BCL-2 family members regulate IP3R-1 phosphorylation to control the rate of ER Ca(2+) leak from intracellular stores.

Pubmed ID: 15613488


  • Oakes SA
  • Scorrano L
  • Opferman JT
  • Bassik MC
  • Nishino M
  • Pozzan T
  • Korsmeyer SJ


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

January 4, 2005

Associated Grants

  • Agency: NIAID NIH HHS, Id: K08 AI 054650
  • Agency: NCI NIH HHS, Id: R37 CA 50239
  • Agency: Telethon, Id: TCP02016

Mesh Terms

  • Animals
  • Apoptosis
  • Calcium
  • Calcium Channels
  • Calcium-Transporting ATPases
  • Endoplasmic Reticulum
  • Inositol 1,4,5-Trisphosphate Receptors
  • Membrane Proteins
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Cytoplasmic and Nuclear
  • Thapsigargin
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein