Endogenously bound calmodulin is essential for the function of the inositol 1,4,5-trisphosphate receptor

doi:10.1074/jbc.M510971200

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Papers In Press, published online ahead of print January 12, 2006
J. Biol. Chem, 10.1074/jbc.M510971200
Submitted on October 7, 2005
Accepted on January 12, 2006

Endogenously bound calmodulin is essential for the function of the inositol 1,4,5-trisphosphate receptor

Nael Nadif Kasri, Katalin Török, Antony Galione, Clive Garnham, Geert Callewaert, Ludwig Missiaen, Jan B. Parys, and Humbert De Smedt

Physiology Dept., K.U.Leuven, Leuven 3000

Corresponding Author: nael.nadifkasri{at}med.kuleuven.be

Calmodulin (CaM) is a ubiquitous Ca2+-sensor protein that plays an important role in regulating a large number of Ca2+ channels, including the inositol 1,4,5-trisphosphate receptor (IP3R). Despite many efforts, the exact mechanism by which CaM regulates the IP3R still remains elusive. Here we show, by using unidirectional 45Ca2+-flux experiments on permeabilized L15 fibroblasts and COS-1 cells, that endogenously bound CaM is essential for the proper activation of the IP3R. Removing endogenously bound CaM by titration with a high-affinity (pmolar) CaM-binding peptide derived from smooth muscle myosin light-chain kinase (MLCK peptide) strongly inhibited IP3-induced Ca2+ release (IICR). This inhibition was concentration and time dependent. Removing endogenously bound CaM affected the maximal release capacity but not its sensitivity to IP3. A mutant peptide with strongly reduced affinity for CaM did not affect IICR. Furthermore, the inhibition by the MLCK peptide was fully reversible. Re-adding exogenous CaM, but not CaM1234, reactivated the IP3R. These data suggest that by using a specific CaM-binding peptide we removed endogenously bound CaM from a high-affinity CaM-binding site on the IP3R and this resulted in a complete loss of the IP3R activity. Our data support a new model whereby CaM is constitutively associated with the IP3R and functions as an essential subunit for proper functioning of the IP3R.

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