Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding

Spencer J. Richardson, Gregory A. Steele, Esther M. Gallant, Alexander Lam, Charles E. Schwartz, Philip G. Board, Marco G. Casarotto, Nicole A. Beard, Angela F. Dulhunty

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    Ryanodine receptor (RyR)Ca2+ channels are central to striatedmuscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated withmyopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of subconductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reducesRyRcurrents in the presence ofWTCLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform-specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca2+ release in this CLIC2 RyR channelopathy.

    Original languageEnglish
    Pages (from-to)3588-3600
    Number of pages13
    JournalJournal of Cell Science
    Volume130
    Issue number20
    DOIs
    Publication statusPublished - 1 Jan 2017

    Fingerprint

    Tacrolimus Binding Proteins
    Ryanodine Receptor Calcium Release Channel
    Protein Binding
    Channelopathies
    Tacrolimus
    Sirolimus
    Nervous System Diseases
    Protein Isoforms

    Cite this

    Richardson, S. J., Steele, G. A., Gallant, E. M., Lam, A., Schwartz, C. E., Board, P. G., ... Dulhunty, A. F. (2017). Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding. Journal of Cell Science, 130(20), 3588-3600. https://doi.org/10.1242/jcs.204461
    Richardson, Spencer J. ; Steele, Gregory A. ; Gallant, Esther M. ; Lam, Alexander ; Schwartz, Charles E. ; Board, Philip G. ; Casarotto, Marco G. ; Beard, Nicole A. ; Dulhunty, Angela F. / Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding. In: Journal of Cell Science. 2017 ; Vol. 130, No. 20. pp. 3588-3600.
    @article{6602d2a35fe14f58922036b310e0fbff,
    title = "Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding",
    abstract = "Ryanodine receptor (RyR)Ca2+ channels are central to striatedmuscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated withmyopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of subconductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reducesRyRcurrents in the presence ofWTCLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform-specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca2+ release in this CLIC2 RyR channelopathy.",
    keywords = "CLIC2, FK506, FKBP12 and FKBP12.6, Ryanodine receptor, RyR channelopathy, Substate opening",
    author = "Richardson, {Spencer J.} and Steele, {Gregory A.} and Gallant, {Esther M.} and Alexander Lam and Schwartz, {Charles E.} and Board, {Philip G.} and Casarotto, {Marco G.} and Beard, {Nicole A.} and Dulhunty, {Angela F.}",
    year = "2017",
    month = "1",
    day = "1",
    doi = "10.1242/jcs.204461",
    language = "English",
    volume = "130",
    pages = "3588--3600",
    journal = "The Quarterly journal of microscopical science",
    issn = "0021-9533",
    publisher = "Company of Biologists Ltd",
    number = "20",

    }

    Richardson, SJ, Steele, GA, Gallant, EM, Lam, A, Schwartz, CE, Board, PG, Casarotto, MG, Beard, NA & Dulhunty, AF 2017, 'Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding', Journal of Cell Science, vol. 130, no. 20, pp. 3588-3600. https://doi.org/10.1242/jcs.204461

    Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding. / Richardson, Spencer J.; Steele, Gregory A.; Gallant, Esther M.; Lam, Alexander; Schwartz, Charles E.; Board, Philip G.; Casarotto, Marco G.; Beard, Nicole A.; Dulhunty, Angela F.

    In: Journal of Cell Science, Vol. 130, No. 20, 01.01.2017, p. 3588-3600.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding

    AU - Richardson, Spencer J.

    AU - Steele, Gregory A.

    AU - Gallant, Esther M.

    AU - Lam, Alexander

    AU - Schwartz, Charles E.

    AU - Board, Philip G.

    AU - Casarotto, Marco G.

    AU - Beard, Nicole A.

    AU - Dulhunty, Angela F.

    PY - 2017/1/1

    Y1 - 2017/1/1

    N2 - Ryanodine receptor (RyR)Ca2+ channels are central to striatedmuscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated withmyopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of subconductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reducesRyRcurrents in the presence ofWTCLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform-specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca2+ release in this CLIC2 RyR channelopathy.

    AB - Ryanodine receptor (RyR)Ca2+ channels are central to striatedmuscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated withmyopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of subconductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reducesRyRcurrents in the presence ofWTCLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform-specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca2+ release in this CLIC2 RyR channelopathy.

    KW - CLIC2

    KW - FK506

    KW - FKBP12 and FKBP12.6

    KW - Ryanodine receptor

    KW - RyR channelopathy

    KW - Substate opening

    UR - http://www.scopus.com/inward/record.url?scp=85031401248&partnerID=8YFLogxK

    U2 - 10.1242/jcs.204461

    DO - 10.1242/jcs.204461

    M3 - Article

    VL - 130

    SP - 3588

    EP - 3600

    JO - The Quarterly journal of microscopical science

    JF - The Quarterly journal of microscopical science

    SN - 0021-9533

    IS - 20

    ER -