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Article Dans Une Revue Biochemical Journal Année : 2008

A calmodulin antagonist reveals a calmodulin-independent inter-domain interaction essential for activation of inositol 1,4,5-trisphosphate receptors

Yi Sun
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Colin W Taylor
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Résumé

Calmodulin (CaM) has been implicated in the regulation of inositol 1,4,5-trisphosphate receptors (IP3R) and a recent report suggested that CaM tightly tethered to IP3R was essential for IP3R activation (Nadif Kasri, N. et al., (2006) J. Biol. Chem. 281, 8332-8338). We confirm that a CaM-binding peptide derived from myosin light chain kinase (MLCK) 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 IP3R that binds directly to the N-terminal to uncouple IP3 binding from channel gating. Our results 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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Dates et versions

hal-00479015 , version 1 (30-04-2010)

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Yi Sun, Colin W Taylor. A calmodulin antagonist reveals a calmodulin-independent inter-domain interaction essential for activation of inositol 1,4,5-trisphosphate receptors. Biochemical Journal, 2008, 416 (2), pp.243-253. ⟨10.1042/BJ20080861⟩. ⟨hal-00479015⟩

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