Skip to content

Research at St Andrews

FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6

Research output: Contribution to journalArticle

Author(s)

Elena Galfre, Samantha Jane Pitt, Elisa Venturi, Mano Sitsapesan, Nathan R Zaccai, Krasimira Tsaneva-Atanasova, Stephen O'Neill, Rebecca Sitsapesan

School/Research organisations

Abstract

Changes in FKBP12.6 binding to cardiac ryanodine receptors (RyR2) are implicated in mediating disturbances in Ca2+-homeostasis in heart failure but there is controversy over the functional effects of FKBP12.6 on RyR2 channel gating. We have therefore investigated the effects of FKBP12.6 and another structurally similar molecule, FKBP12, which is far more abundant in heart, on the gating of single sheep RyR2 channels incorporated into planar phospholipid bilayers and on spontaneous waves of Ca2+-induced Ca2+-release in rat isolated permeabilised cardiac cells. We demonstrate that FKBP12 is a high affinity activator of RyR2, sensitising the channel to cytosolic Ca2+, whereas FKBP12.6 has very low efficacy, but can antagonise the effects of FKBP12. Mathematical modelling of the data shows the importance of the relative concentrations of FKBP12 and FKBP12.6 in determining RyR2 activity. Consistent with the single-channel results, physiological concentrations of FKBP12 (3 µM) increased Ca2+-wave frequency and decreased the SR Ca2+-content in cardiac cells. FKBP12.6, itself, had no effect on wave frequency but antagonised the effects of FKBP12.We provide a biophysical analysis of the mechanisms by which FK-binding proteins can regulate RyR2 single-channel gating. Our data indicate that FKBP12, in addition to FKBP12.6, may be important in regulating RyR2 function in the heart. In heart failure, it is possible that an alteration in the dual regulation of RyR2 by FKBP12 and FKBP12.6 may occur. This could contribute towards a higher RyR2 open probability, 'leaky' RyR2 channels and Ca2+-dependent arrhythmias.

Close

Details

Original languageEnglish
Article numbere31956
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - 21 Feb 2012

    Research areas

  • Calcium-release channel, FKBP, Heart disease, Arrhythmia

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Total plasma magnesium, zinc, copper and selenium concentrations in type-I and type-II diabetes

    Sobczak, A. I. S., Stefanowicz, F., Pitt, S. J., Ajjan, R. A. & Stewart, A. J. 26 Dec 2018 (Accepted/In press) In : BioMetals. In press

    Research output: Contribution to journalArticle

  2. Influence of zinc on glycosaminoglycan neutralisation during coagulation

    Sobczak, A. I. S., Pitt, S. J. & Stewart, A. J. Sep 2018 In : Metallomics. 10, 9, p. 1180-1190 11 p.

    Research output: Contribution to journalReview article

  3. Glycosaminoglycan neutralization in coagulation control

    Sobczak, A. I. S., Pitt, S. J. & Stewart, A. J. Jun 2018 In : Arteriosclerosis, Thrombosis, and Vascular Biology. 38, 6, p. 1258-1270 14 p.

    Research output: Contribution to journalReview article

  4. Modulation of the Neisseria gonorrhoeae drug efflux conduit MtrE

    Tamburrino, G., Llabrés, S., Vickery, O., Pitt, S. J. & Zachariae, U. 6 Dec 2017 In : Scientific Reports. 7, 10 p., 17091

    Research output: Contribution to journalArticle

  5. Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high fat diet

    Jovanovic, A., Obradovic, M., Sudar-Milovanovic, E., Stewart, A. J., Pitt, S. J., Alvantic, D., Aleksic, E. & Isenovic, E. R. Dec 2017 In : Molecular and Cellular Biochemistry. 436, 1-2, p. 49-58 10 p.

    Research output: Contribution to journalArticle

Related by journal

  1. PLoS One (Journal)

    Cross, C. P. (Member of editorial board)
    1 Sep 2018 → …

    Activity: Publication peer-review and editorial workEditor of research journal

  2. PLoS One (Journal)

    Cresswell, W. (Reviewer)
    23 May 2018

    Activity: Publication peer-review and editorial workPeer review of manuscripts

  3. PLoS ONE (Journal)

    Dritschel, B. (Member of editorial board)
    May 2018 → …

    Activity: Publication peer-review and editorial workEditor of research journal

  4. PLoS One (Journal)

    Young, S. (Reviewer)
    7 Jun 201719 Jun 2017

    Activity: Publication peer-review and editorial workPeer review of manuscripts

  5. PLoS ONE (Journal)

    Schwarz-Linek, U. (Reviewer)
    Mar 2017

    Activity: Publication peer-review and editorial workPeer review of manuscripts

Related by journal

  1. Agreement between primary care and hospital diagnosis of schizophrenia and bipolar disorder: a cross-sectional, observational study using record linkage

    O’Neill, B., Kalia, S., Aliarzadeh, B., Moineddin, R., Fung, W. L. A., Sullivan, F., Maloul, A., Bernard, S. & Greiver, M. 7 Jan 2019 In : PLoS ONE. 14, 1, 15 p., e0210214

    Research output: Contribution to journalArticle

  2. Molecular epidemiology and expression of capsular polysaccharides in Staphylococcus aureus clinical isolates in the United States

    Mohamed, N. , Timofeyeva, Y. , Jamrozy, D. , Rojas, E. , Hao, L. , Silmon de Monerri, N. C. , Hawkins, J. , Singh, G. , Cai, B. , Liberator, P. , Sebastian, S. , Donald, R. G. K. , Scully, I. L. , Jones, C. H. , Creech, C. B. , Thomsen, I. , Parkhill, J. , Peacock, S. J. , Jansen, K. U. , Holden, M. T. G. & 1 others Anderson, A. S. 14 Jan 2019 In : PLoS ONE. 14, 1, 33 p., e0208356

    Research output: Contribution to journalArticle

  3. 16S rRNA gene metabarcoding and TEM reveals different ecological strategies within the genus Neogloboquadrina (planktonic foraminifer)

    Bird, C., Darling, K. F., Russell, A. D., Fehrenbacher, J. S., Davis, C. V., Free, A. & Ngwenya, B. T. 29 Jan 2018 In : PLoS One. 13, 1, 26 p., e0191653

    Research output: Contribution to journalArticle

  4. Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib

    Ladds, M. J. G. W., Pastor-Fernández, A., Popova, G., van Leeuwen, I. M. M., Eng, K. E., Drummond, C. J., Johansson, L., Svensson, R., Westwood, N. J., McCarthy, A. R., Tholander, F., Popa, M., Lane, D. P., McCormack, E., McInerney, G. M., Bhatia, R. & Laín, S. 23 Apr 2018 In : PLoS One. 13, 4, 21 p., e0195956

    Research output: Contribution to journalArticle

  5. Body density of humpback whales (Megaptera novaengliae) in feeding aggregations estimated from hydrodynamic gliding performance

    Narazaki, T., Isojunno, S., Nowacek, D. P., Swift, R., Friedlaender, A. S., Ramp, C., Smout, S., Aoki, K., Deecke, V. B., Sato, K. & Miller, P. J. O. 12 Jul 2018 In : PLoS ONE. 13, 7, 23 p., e0200287

    Research output: Contribution to journalArticle

ID: 48756016