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

Journal article

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: Kasri, N; Holmes, A; Bultynck, G; Parys, J; Bootman, MD

• Publication status: Published
• Journal: EMBO journal
• Volume: 23
• Issue: 2
• Pages: 312-321
• Publication date: 2004-01-01
• DOI: 10.1038/sj.emboj.7600037
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: Cercopithecus aethiops; Xenopus laevis; Amino Acid Sequence; Neurons; Calcium-Binding Proteins; Inositol 1,4,5-Trisphosphate Receptors; Oocytes; Inositol 1,4,5-Trisphosphate; Animals; Calcium Signaling; Calcium Channels; COS Cells; Receptors, Cytoplasmic and Nuclear; Phosphorylation; Molecular Sequence Data; Binding Sites