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Buckley, Charlotte; Wilson, Calum; McCarron, John G.

FK506 regulates Ca2+ release evoked by inositol 1,4,5‐trisphosphate independently of FK‐binding protein in endothelial cells

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  • Medientyp: E-Artikel
  • Titel: FK506 regulates Ca2+ release evoked by inositol 1,4,5‐trisphosphate independently of FK‐binding protein in endothelial cells
  • Beteiligte: Buckley, Charlotte; Wilson, Calum; McCarron, John G.
  • Erschienen: Wiley, 2020
  • Erschienen in: British Journal of Pharmacology, 177 (2020) 5, Seite 1131-1149
  • Sprache: Englisch
  • DOI: 10.1111/bph.14905
  • ISSN: 0007-1188; 1476-5381
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Background and Purpose</jats:title><jats:p>FK506 and rapamycin are modulators of FK‐binding proteins (FKBP) that are used to suppress immune function after organ and hematopoietic stem cell transplantations. The drugs share the unwanted side‐effect of evoking hypertension that is associated with reduced endothelial function and nitric oxide production. The underlying mechanisms are not understood. FKBP may regulate IP<jats:sub>3</jats:sub> receptors (IP<jats:sub>3</jats:sub>R) and ryanodine receptors (RyR) to alter Ca<jats:sup>2+</jats:sup> signalling in endothelial cells.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>We investigated the effects of FK506 and rapamycin on Ca<jats:sup>2+</jats:sup> release via IP<jats:sub>3</jats:sub>R and RyR in hundreds of endothelial cells, using the indicator Cal‐520, in intact mesenteric arteries from male Sprague‐Dawley rats. IP<jats:sub>3</jats:sub>Rs were activated by acetylcholine or localised photo‐uncaging of IP<jats:sub>3</jats:sub>, and RyR by caffeine.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>While FKBPs were present, FKBP modulation with rapamycin did not alter IP<jats:sub>3</jats:sub>‐evoked Ca<jats:sup>2+</jats:sup> release. Conversely, FK506, which modulates FKBP and blocks calcineurin, increased IP<jats:sub>3</jats:sub>‐evoked Ca<jats:sup>2+</jats:sup> release. Inhibition of calcineurin (okadiac acid or cypermethrin) also increased IP<jats:sub>3</jats:sub>‐evoked Ca<jats:sup>2+</jats:sup> release and blocked FK506 effects. When calcineurin was inhibited, FK506 reduced IP<jats:sub>3</jats:sub>‐evoked Ca<jats:sup>2+</jats:sup> release. These findings suggest that IP<jats:sub>3</jats:sub>‐evoked Ca<jats:sup>2+</jats:sup> release is not modulated by FKBP, but by FK506‐mediated calcineurin inhibition. The RyR modulators caffeine and ryanodine failed to alter Ca<jats:sup>2+</jats:sup> signalling suggesting that RyR is not functional in native endothelium.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>The hypertensive effects of the immunosuppressant drugs FK506 and rapamycin, while mediated by endothelial cells, do not appear to be exerted at the documented cellular targets of Ca<jats:sup>2+</jats:sup> release and altered FKBP binding to IP<jats:sub>3</jats:sub> and RyR.</jats:p></jats:sec>
  • Zugangsstatus: Freier Zugang