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PNAS 99 (11): 7711-7716

Copyright © 2002 by the National Academy of Sciences.

From the Cover


Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels

Jun Yang*, Sean McBride*, Don-On Daniel Mak*, Noga Vardi{dagger}, Krzysztof Palczewski{ddagger},§, Françoise Haeseleer{ddagger}, and J. Kevin Foskett*,||

Departments of *Physiology and {dagger}Neuroscience, University of Pennsylvania, Philadelphia, PA 19104-6085; and Departments of {ddagger}Ophthalmology, §Pharmacology, and Chemistry, University of Washington, Seattle, WA 98195

Received for publication January 4, 2002.

Abstract: 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 InsP3R channel is normally thought to require binding of InsP3 derived 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 InsP3R channel isoforms with high affinity (Ka {approx} 25 nM) in a Ca2+-dependent manner (Ka {approx} 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 InsP3R associate 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 InsP3 generation, 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.

|| To whom reprint requests should be addressed. E-mail: foskett{at}

Edited by David H. MacLennan, University of Toronto, Toronto, Canada, and approved March 26, 2002

This paper was submitted directly (Track II) to the PNAS office.

See commentary on page 7320.

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