Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca(2+) release channels

Proc Natl Acad Sci U S A. 2002 May 28;99(11):7711-6. doi: 10.1073/pnas.102006299.


The inositol trisphosphate (InsP(3)) receptor (InsP(3)R) is a ubiquitously expressed intracellular Ca(2+) channel that mediates complex cytoplasmic Ca(2+) signals, regulating diverse cellular processes, including synaptic plasticity. Activation of the InsP(3)R channel is normally thought to require binding of InsP(3) derived from receptor-mediated activation of phosphatidylinositol lipid hydrolysis. Here we identify a family of neuronal Ca(2+)-binding proteins as high-affinity protein agonists of the InsP(3)R, which bind to the channel and activate gating in the absence of InsP(3). CaBP/caldendrin, a subfamily of the EF-hand-containing neuronal calcium sensor family of calmodulin-related proteins, bind specifically to the InsP(3)-binding region of all three InsP(3)R channel isoforms with high affinity (K(a) approximately 25 nM) in a Ca(2+)-dependent manner (K(a) approximately 1 microM). Binding activates single-channel gating as efficaciously as InsP(3), dependent on functional EF-hands in CaBP. In contrast, calmodulin neither bound with high affinity nor activated channel gating. CaBP1 and the type 1 InsP(3)R associate in rat whole brain and cerebellum lysates, and colocalize extensively in subcellular regions in cerebellar Purkinje neurons. Thus, InsP(3)R-mediated Ca(2+) signaling in cells is possible even in the absence of InsP(3) generation, a process that may be particularly important in responding to and shaping changes in intracellular Ca(2+) concentration by InsP(3)-independent pathways and for localizing InsP(3)-mediated Ca(2+) signals to individual synapses.

Publication types

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

MeSH terms

  • Animals
  • Brain / physiology*
  • Calcium Channels / physiology*
  • Calcium-Binding Proteins / metabolism*
  • Cell Membrane / physiology
  • Cell Nucleus / physiology
  • DNA, Complementary
  • Female
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ligands
  • Membrane Potentials / physiology
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Rats
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Retina / physiology
  • Xenopus laevis


  • Calcium Channels
  • Calcium-Binding Proteins
  • DNA, Complementary
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ligands
  • Receptors, Cytoplasmic and Nuclear