title: Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins.
abstract: Inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) were recently demonstrated to be activated independently of InsP(3) by a family of calmodulin (CaM)-like neuronal Ca(2+)-binding proteins (CaBPs). We investigated the interaction of both naturally occurring long and short CaBP1 isoforms with InsP(3)Rs, and their functional effects on InsP(3)R-evoked Ca(2+) signals. Using several experimental paradigms, including transient expression in COS cells, acute injection of recombinant protein into Xenopus oocytes and (45)Ca(2+) flux from permeabilised COS cells, we demonstrated that CaBPs decrease the sensitivity of InsP(3)-induced Ca(2+) release (IICR). In addition, we found a Ca(2+)-independent interaction between CaBP1 and the NH(2)-terminal 159 amino acids of the type 1 InsP(3)R. This interaction resulted in decreased InsP(3) binding to the receptor reminiscent of that observed for CaM. Unlike CaM, however, CaBPs do not inhibit ryanodine receptors, have a higher affinity for InsP(3)Rs and more potently inhibited IICR. We also show that phosphorylation of CaBP1 at a casein kinase 2 consensus site regulates its inhibition of IICR. Our data suggest that CaBPs are endogenous regulators of InsP(3)Rs tuning the sensitivity of cells to InsP(3).
authors.affiliation: Laboratorium voor Fysiologie, KU Leuven, Campus Gasthuisberg O/N, Leuven, Belgium.
authors.forename: Nael Nadif
authors.initials: NN
authors.lastname: Kasri
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Holmes
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Martin D
authors.initials: MD
authors.lastname: Bootman
authors.forename: Katja
authors.initials: K
authors.lastname: Rietdorf
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.forename: Fraser
authors.initials: F
authors.lastname: McDonald
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Holmes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Berridge
authors.forename: H Llewelyn
authors.initials: HL
authors.lastname: Roderick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D002522:Chlorocebus aethiops; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate