Inhibition of inositol trisphosphate-induced calcium release by cyclicADP-ribose in A7r5 smooth-muscle cells and in 16HBE14o- bronchial mucosal cells

Author:

MISSIAEN Ludwig1,PARYS B. Jan1,SMEDT Humbert DE1,SIENAERT Ilse1,SIPMA Henk1,VANLINGEN Sara1,MAES Karlien1,KUNZELMANN Karl2,CASTEELS Rik1

Affiliation:

1. Laboratorium voor Fysiologie, K.U. Leuven Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

2. Physiologisches Institut der Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Strasse 7, D-79104 Freiburg, Germany

Abstract

Ca2+ release from intracellular stores occurs via two families of intracellular channels, each with their own specific agonist: Ins(1,4,5)P3 for the Ins(1,4,5)P3 receptor and cyclic ADP-ribose (cADPR) for the ryanodine receptor. We now report that cADPR inhibited Ins(1,4,5)P3-induced Ca2+ release in permeabilized A7r5 cells with an IC50 of 20 μM, and in permeabilized 16HBE14o- bronchial mucosal cells with an IC50 of 35 μM. This inhibition was accompanied by an increase in specific [3H]Ins(1,4,5)P3 binding. 8-Amino-cADPR, but not 8-bromo-cADPR, antagonized this effect of cADPR. The inhibition was prevented by a whole series of inositol phosphates (10 μM) that did not affect Ins(1,4,5)P3-induced Ca2+ release, and by micromolar concentrations of PPi and various nucleotide di- or triphosphates. We propose that cADPR must interact with a novel regulatory site on the Ins(1,4,5)P3 receptor or on an associated protein. This site is neither the Ins(1,4,5)P3-binding domain, which prefers Ins(1,4,5)P3 and only binds nucleotides and PPi in the millimolar range, nor the stimulatory adenine nucleotide binding site.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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