IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor.
The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-gated intracellular Ca2+ channels. We previously identified an IP3R binding protein, IRBIT, which binds to the IP3 binding domain of IP3R and is dissociated from IP3R in the presence of IP3. In the present study, we showed that IRBIT suppresses the activation of IP3R by competing with IP3 by [3H]IP3 binding assays, in vitro Ca2+ release assays, and Ca2+ imaging of intact cells. Multiserine phosphorylation of IRBIT was essential for the binding, and 10 of the 12 key amino acids in IP3R for IP3 recognition participated in binding to IRBIT. We propose a unique mode of IP3R regulation in which IP3 sensitivity is regulated by IRBIT acting as an endogenous "pseudoligand" whose inhibitory activity can be modulated by its phosphorylation status.
Ando
Hideaki
H
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Saitama 351-0198.
Mizutani
Akihiro
A
Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639.
Kiefer
Hélène
H
Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639.
Tsuzurugi
Dai
D
Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639.
Michikawa
Takayuki
T
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Saitama 351-0198; Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639; Calcium Oscillation Project, International Cooperative Research Project-Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Mikoshiba
Katsuhiko
K
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Saitama 351-0198; Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639; Calcium Oscillation Project, International Cooperative Research Project-Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. Electronic address: mikosiba@ims.u-tokyo.ac.jp.
D043383:Adenosylhomocysteinase / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D012694:Serine / Q000378:metabolism
C470184:CLECL1 protein, human; D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012694:Serine; D015544:Inositol 1,4,5-Trisphosphate; D043383:Adenosylhomocysteinase; D002118:Calcium