title: Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals.
abstract: The antiapoptotic protein Bcl-2 inhibits Ca2+ release from the endoplasmic reticulum (ER). One proposed mechanism involves an interaction of Bcl-2 with the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel localized with Bcl-2 on the ER. Here we document Bcl-2-IP3R interaction within cells by FRET and identify a Bcl-2 interacting region in the regulatory and coupling domain of the IP3R. A peptide based on this IP3R sequence displaced Bcl-2 from the IP3R and reversed Bcl-2-mediated inhibition of IP3R channel activity in vitro, IP3-induced ER Ca2+ release in permeabilized cells, and cell-permeable IP3 ester-induced Ca2+ elevation in intact cells. This peptide also reversed Bcl-2's inhibition of T cell receptor-induced Ca2+ elevation and apoptosis. Thus, the interaction of Bcl-2 with IP3Rs contributes to the regulation of proapoptotic Ca2+ signals by Bcl-2, suggesting the Bcl-2-IP3R interaction as a potential therapeutic target in diseases associated with Bcl-2's inhibition of cell death.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Rong
authors.forename: Ademuyiwa S
authors.initials: AS
authors.lastname: Aromolaran
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Fei
authors.initials: F
authors.lastname: Zhong
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Karen
authors.initials: K
authors.lastname: McColl
authors.forename: Shigemi
authors.initials: S
authors.lastname: Matsuyama
authors.forename: Stephan
authors.initials: S
authors.lastname: Herlitze
authors.forename: H Llewelyn
authors.initials: HL
authors.lastname: Roderick
authors.forename: Martin D
authors.initials: MD
authors.lastname: Bootman
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Mignery
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.forename: Clark W
authors.initials: CW
authors.lastname: Distelhorst
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D019556:COS Cells; D020013:Calcium Signaling / Q000187:drug effects; D002522:Chlorocebus aethiops; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell