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

Autor:	John G. McCarron, Charlotte Buckley, Calum Wilson
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine inorganic chemicals Male Endothelium Inositol 1 4 5-Trisphosphate Tacrolimus Nitric oxide Rats Sprague-Dawley Tacrolimus Binding Proteins 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Inositol Receptor Pharmacology Ryanodine receptor Endothelial Cells Ryanodine Receptor Calcium Release Channel Research Papers 3. Good health Cell biology Rats Calcineurin 030104 developmental biology FKBP medicine.anatomical_structure chemistry cardiovascular system Calcium 030217 neurology & neurosurgery Acetylcholine medicine.drug Research Paper
Zdroj:	British Journal of Pharmacology
ISSN:	1476-5381 0007-1188
Popis:	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 receptors (IP3 R) and ryanodine receptors (RyR) to alter Ca2+ signalling in endothelial cells. Experimental approach We investigated the effects of FK506 and rapamycin on Ca2+ release via IP3 R and RyR in hundreds of endothelial cells, using the indicator Cal-520, in intact mesenteric arteries from male Sprague-Dawley rats. IP3 Rs were activated by acetylcholine or localised photo-uncaging of IP3 , and RyR by caffeine. Key results While FKBPs were present, FKBP modulation with rapamycin did not alter IP3 -evoked Ca2+ release. Conversely, FK506, which modulates FKBP and blocks calcineurin, increased IP3 -evoked Ca2+ release. Inhibition of calcineurin (okadiac acid or cypermethrin) also increased IP3 -evoked Ca2+ release and blocked FK506 effects. When calcineurin was inhibited, FK506 reduced IP3 -evoked Ca2+ release. These findings suggest that IP3 -evoked Ca2+ release is not modulated by FKBP, but by FK506-mediated calcineurin inhibition. The RyR modulators caffeine and ryanodine failed to alter Ca2+ signalling 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 the documented cellular targets of Ca2+ release and altered FKBP binding to IP3 and RyR.
Databáze:	OpenAIRE
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