Strathprints Home | Open Access | Browse | Search | User area | Copyright | Help | Library Home | SUPrimo

Regulation by FK506 and rapamycin of Ca2+ release from the sarcoplasmic reticulum in vascular smooth muscle : the role of FK506 binding proteins and mTOR

MacMillan, D. and McCarron, J.G. (2009) Regulation by FK506 and rapamycin of Ca2+ release from the sarcoplasmic reticulum in vascular smooth muscle : the role of FK506 binding proteins and mTOR. British Journal of Pharmacology, 158 (4). pp. 1112-1120. ISSN 0007-1188

Full text not available in this repository. (Request a copy from the Strathclyde author)

Abstract

Background and purpose: The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca2+ concentration ([Ca2+]cyto) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). These receptors may be regulated by the accessory FK506-binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR). Experimental approach: Single portal vein myocytes were voltage-clamped in whole cell configuration and [Ca2+]cyto measured using fluo-3. IP3Rs were activated by photolysis of caged IP3 and RyRs activated by hydrostatic application of caffeine. Key results: FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca2+]cyto rise evoked by activation of either RyR or IP3R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine-evoked, but reduced the IP3-evoked [Ca2+]cyto rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine- or IP3-evoked [Ca2+]cyto release; calcineurin did not contribute to FK506-mediated potentiation of RyR- or IP3R-mediated Ca2+ release. The mTOR inhibitor LY294002, like rapamycin, decreased IP3-evoked Ca2+ release. Conclusions and implications: Ca2+ release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP3R-mediated Ca2+ release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP3-mediated Ca2+ release may be explained by mTOR inhibition.

Item type: Article
ID code: 18928
Keywords: FK506, rapamycin, FK506-binding proteins, ryanodine receptor, inositol 1, 4, 5-trisphosphate receptor, mTOR, calcineurin, vascular smooth muscle, calcium, Therapeutics. Pharmacology, Pharmacy and materia medica, Pharmacology
Subjects: Medicine > Therapeutics. Pharmacology
Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Strathprints Administrator
    Date Deposited: 21 Jun 2010 11:20
    Last modified: 05 Sep 2014 03:59
    URI: http://strathprints.strath.ac.uk/id/eprint/18928

    Actions (login required)

    View Item