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Benoit DevogelaereIRBIT, a novel regulator in Ca2+ signalling

Abstract :


The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is located in the endoplasmic reticulum, an intracellular Ca2+ storage place.
The IP3R mediates Ca2+ release into the cytoplasm in response to IP3 production. IRBIT is a recently discovered IP3R-binding protein that can be released from the IP3R by binding of IP3 to the IP3R. Both IP3R type 1 and IRBIT are predominantly expressed in brain tissue, and inactivation of IP3R type 1 is associated with severe neurological disorders. We have identified IRBIT as a novel inhibitor of the IP3-induced Ca2+ release: IRBIT inhibits the binding of IP3 to the IP3R, and thereby decreases the IP3R-mediated Ca2+ release. Furthermore we have elucidated the interaction mechanism between IRBIT and the IP3R: we found that phosphorylation of IRBIT is essential for a direct interaction between IRBIT and the IP3R, and we identified three critical phosphorylation sites. We also showed that protein phosphatase-1 (PP1) is a novel interaction partner of IRBIT, and pinpointed an inhibitory role for PP1-mediated dephosphorylation of IRBIT in the interaction of IRBIT with the IP3R. As the interaction of IRBIT with the IP3R is also regulated by pH, this makes IRBIT in an excellent position to act as a molecular switch that translates cellular input signals (phosphorylation cascades and pH effects) into an appropriate Ca2+ signal.

Selected publications

Devogelaere B, Beullens M, Sammels E, Derua R, Waelkens E, van Lint J, Parys JB, Missiaen L, Bollen M, De Smedt H.
Protein phosphatase-1 is a novel regulator of the interaction between IRBIT and the inositol 1,4,5-trisphosphate receptor.
Biochem J. 2007 Oct 15;407(2):303-11.
Devogelaere B, Verbert L, Parys JB, Missiaen L, De Smedt H.
The complex regulatory function of the ligand-binding domain of the inositol 1,4,5-trisphosphate receptor.
Cell Calcium. 2007 May 11; [Epub ahead of print]
Ashworth R, Devogelaere B, Fabes J, Tunwell RE, Koh KR, De Smedt H, Patel S.
Molecular and functional characterization of inositol trisphosphate receptors during early zebrafish development.
J Biol Chem. 2007 May 11;282(19):13984-93. Epub 2007 Mar 1.
Devogelaere B, Nadif Kasri N, Derua R, Waelkens E, Callewaert G, Missiaen L, Parys JB, De Smedt H.
Binding of IRBIT to the IP3 receptor: determinants and functional effects.
Biochem Biophys Res Commun. 2006 Apr 28;343(1):49-56. Epub 2006 Feb 28.

Jean Luc Morel