Identification of a Family of Calcium Sensors as Protein Ligands of Inositol Trisphosphate Receptor Ca2+Release Channels

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-05, Vol.99 (11), p.7711-7716
• Main Authors: Yang, Jun, McBride, Sean, Mak, Don-On Daniel, Vardi, Noga, Palczewski, Krzysztof, Haeseleer, Françoise, Foskett, J. Kevin
• Format: Article
• Language: English
• Subjects: Antibodies; Biological Sciences; Biology; Brain; Calcium; COS cells; Ligands; Neurons; Oocytes; Pipettes; Protein isoforms; Proteins; Purkinje cells; Receptors; Sensors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.102006299

The inositol trisphosphate (InsP3) receptor (InsP3R) is a ubiquitously expressed intracellular Ca2+channel that mediates complex cytoplasmic Ca2+signals, regulating diverse cellular processes, including synaptic plasticity. Activation of the InsP3Rchannel is normally thought to require binding of InsP3derived from receptor-mediated activation of phosphatidylinositol lipid hydrolysis. Here we identify a family of neuronal Ca2+-binding proteins as high-affinity protein agonists of the InsP3R, which bind to the channel and activate gating in the absence of InsP3. CaBP/caldendrin, a subfamily of the EF-hand-containing neuronal calcium sensor family of calmodulin-related proteins, bind specifically to the InsP3-binding region of all three InsP3Rchannel isoforms with high affinity (Ka≈ 25 nM) in a Ca2+-dependent manner (Ka≈ 1 µM). Binding activates single-channel gating as efficaciously as InsP3, dependent on functional EF-hands in CaBP. In contrast, calmodulin neither bound with high affinity nor activated channel gating. CaBP1 and the type 1 InsP3Rassociate in rat whole brain and cerebellum lysates, and colocalize extensively in subcellular regions in cerebellar Purkinje neurons. Thus, InsP3R-mediated Ca2+signaling in cells is possible even in the absence of InsP3generation, a process that may be particularly important in responding to and shaping changes in intracellular Ca2+concentration by InsP3-independent pathways and for localizing InsP3-mediated Ca2+signals to individual synapses.