title: Unraveling the role of polycystin-2/inositol 1,4,5-trisphosphate receptor interaction in Ca signaling.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) arises as a consequence of mutations of the genes PKD1 and PKD2, encoding respectively the integral membrane proteins polycystin-1 and polycystin-2 (TRPP2), resulting in a disturbance in intracellular Ca(2+) signaling. Previously we investigated the interaction between TRPP2 and the inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R), an intracellular Ca(2+) channel in the endoplasmic reticulum (ER). We identified the molecular determinants of this interaction and observed an enhanced IP(3)-induced Ca(2+) release (IICR). Since we found that TRPP2 strongly bound to a cluster of positively charged amino acids in the N-terminal ligand-binding domain (LBD) of the IP(3)R, we now investigated whether TRPP2 would interfere with the binding of IP(3) to the IP(3)R. In in vitro experiments we observed that TRPP2 partially inhibited the binding of IP(3) to the LBD of the IP(3)R with an IC(50) of ∼350 nM. The suppressor domain, i.e., the N-terminal 225 amino acids of the LBD of the IP(3)R, mediated this inhibitory effect of TRPP2 on IP(3) binding. The observation that the interaction between the IP(3)R and TRPP2 decreased IP(3) binding is in apparent contrast to the increased IICR. The data can be explained however by a subsequent activation of Ca(2+)-induced Ca(2+) release (CICR) via TRPP2. Implications of this mechanism for cellular Ca(2+) signaling are discussed in this addendum.
authors.affiliation: Laboratory of Molecular and Cellular Signaling; Department of Molecular Cell Biology; K.U. Leuven, Leuven Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Sammels
authors.forename: Benoit
authors.initials: B
authors.lastname: Devogelaere
authors.forename: Djalila
authors.initials: D
authors.lastname: Mekahli
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt