Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins

NN Kasri, AM Holmes, G Bultynck, JB Parys, MD Bootman, K Rietdorf, L Missiaen, F McDonald, H De Smedt, Stuart John Conway, AB Holmes, MJ Berridge, HL Roderick

Research output: Contribution to journalArticlepeer-review

131 Citations (Scopus)

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 Ca2+-binding proteins (CaBPs). We investigated the interaction of both naturally occurring long and short CaBP1 isoforms with InsP3Rs, and their functional effects on InsP(3)R-evoked Ca2+ signals. Using several experimental paradigms, including transient expression in COS cells, acute injection of recombinant protein into Xenopus oocytes and Ca-45(2+) flux from permeabilised COS cells, we demonstrated that CaBPs decrease the sensitivity of InsP(3)-induced Ca2+ release (IICR). In addition, we found a Ca2+-independent interaction between CaBP1 and the NH2-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).

Original languageEnglish
Pages (from-to)312-321
Number of pages10
JournalEMBO Journal
Volume23
Issue number2
DOIs
Publication statusPublished - 28 Jan 2004

Keywords

  • Ca2+
  • CaBP
  • InsP(3)
  • signalling
  • INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR
  • BASOPHILIC LEUKEMIA-CELLS
  • CALCIUM-RELEASE CHANNELS
  • ENDOPLASMIC-RETICULUM
  • TRISPHOSPHATE RECEPTORS
  • PURKINJE NEURONS
  • CA2+-INDEPENDENT INHIBITION
  • FUNCTIONAL-PROPERTIES
  • CA2+ OSCILLATIONS
  • CYTOSOLIC CA2+

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