FK506 regulates IP3 evoked Ca2+ release independently of FKBP in endothelial cells

Buckley, Charlotte and Wilson, Calum and McCarron, John G. (2019) FK506 regulates IP3 evoked Ca2+ release independently of FKBP in endothelial cells. British Journal of Pharmacology. ISSN 1476-5381 (In Press)

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    Abstract

    Background and Purpose 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 IP3 and ryanodine receptors to alter Ca2+ signalling in endothelial cells. Experimental Approach We investigated the effects of FK506 and rapamycin on Ca2+ release via IP3 and ryanodine receptors in large numbers of endothelial cells in intact arteries. Key Results While confirmed to be present, FKBP modulation with rapamycin did not alter IP3-evoked Ca2+ release. Conversely, FK506, which modulates FKBP and additionally blocks calcineurin, increased IP3-evoked Ca2+ release. Inhibition of calcineurin (using okadiac acid or cypermethrin) also increased IP3-evoked Ca2+ release and blocked FK506 effects. Indeed, when calcineurin was inhibited with okadiac acid, FK506 reduced IP3-evoked Ca2+ release. These findings suggest that FKBP does not modulate IP3-evoked Ca2+ release and FK506 increased IP3-evoked Ca2+ release by calcineurin inhibition. FK506 and rapamycin are also unlikely to mediate their effects via RyR. The RyR activator caffeine and ryanodine itself failed to evoke Ca2+ changes suggesting that RyR is not functional in native endothelium. Conclusion and Implications The hypertensive effects of the immunosuppressant drugs FK506 and rapamycin, while mediated by endothelial cells, do not appear to be exerted at documented cellular targets of the drugs on Ca2+ release and altered FKBP binding to IP3 and RyR.