CaM (calmodulin) has been implicated in the regulation of IP3R [IP3 (inositol 1,4,5-trisphosphate) receptors] and a recent report suggested that CaM tightly tethered to IP3R was essential for IP3R activation [Nadif Kasri, Torok, Galione, Garnham, Callewaert, Missiaen, Parys and De Smedt (2006) J. Biol. Chem. 281, 8332–8338]. In the present study, we confirm that a CaM-binding peptide derived from MLCK (myosin light chain kinase) inhibits IP3-evoked Ca2+ release via all three IP3R subtypes. However, inhibition by MLCK peptide is not mimicked by other CaM antagonists that effectively block regulation of IP3R by CaM. Inhibition by MLCK peptide is rapid, fully reversible and occurs under conditions where there is no CaM associated with IP3R. MLCK peptide stimulates IP3 binding to IP3R1 and to its bacterially expressed N-terminal, but not after removal of the suppressor domain (residues 1–224). We suggest that MLCK peptide mimics a sequence within the suppressor domain that is similar to a 1-8-14 CaM-binding motif. The peptide may thereby unzip an interdomain interaction that is essential for IP3R activation. We conclude that CaM is not essential for IP3R activation, and that MLCK peptide is a selective antagonist of the IP3R that binds directly to the N-terminal to uncouple IP3 binding from channel gating. The results of the present study highlight the importance of the suppressor domain in IP3R activation and suggest that MLCK peptide may provide a route to novel non-competitive antagonists of IP3R.
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Research Article|
November 12 2008
A calmodulin antagonist reveals a calmodulin-independent interdomain interaction essential for activation of inositol 1,4,5-trisphosphate receptors
Yi Sun;
Yi Sun
1Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, U.K.
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Colin W. Taylor
Colin W. Taylor
1
1Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, U.K.
1To whom correspondence should be addressed (email cwt1000@cam.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 28 2008
Revision Received:
July 18 2008
Accepted:
July 21 2008
Accepted Manuscript online:
July 21 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 416 (2): 243–253.
Article history
Received:
April 28 2008
Revision Received:
July 18 2008
Accepted:
July 21 2008
Accepted Manuscript online:
July 21 2008
Citation
Yi Sun, Colin W. Taylor; A calmodulin antagonist reveals a calmodulin-independent interdomain interaction essential for activation of inositol 1,4,5-trisphosphate receptors. Biochem J 1 December 2008; 416 (2): 243–253. doi: https://doi.org/10.1042/BJ20080861
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