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

Research output: Contribution to journalArticle

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.
LanguageEnglish
JournalBritish Journal of Pharmacology
DOIs
Publication statusAccepted/In press - 11 Oct 2019

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Tacrolimus
Carrier Proteins
Endothelial Cells
Sirolimus
Calcineurin
Inositol 1,4,5-Trisphosphate Receptors
Ryanodine Receptor Calcium Release Channel
Pharmaceutical Preparations
Ryanodine
Acids
Hematopoietic Stem Cell Transplantation
Immunosuppressive Agents
Caffeine
Protein Binding
Endothelium
Nitric Oxide
Arteries
Hypertension

Keywords

  • vascular
  • endothelium
  • calcium
  • FKBP
  • FK506
  • rapamycin
  • okadaic acid
  • cypermethrin
  • inositol 1,4,5‐trisphosphate (IP3)
  • ryanodine receptors
  • calcineurin

Cite this

@article{af121d5bb23042d181eecda918bc34a4,
title = "FK506 regulates IP3 evoked Ca2+ release independently of FKBP in endothelial cells",
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 ApproachWe 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 ResultsWhile 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.",
keywords = "vascular, endothelium, calcium, FKBP, FK506, rapamycin, okadaic acid, cypermethrin, inositol 1,4,5‐trisphosphate (IP3), ryanodine receptors, calcineurin",
author = "Charlotte Buckley and Calum Wilson and McCarron, {John G.}",
year = "2019",
month = "10",
day = "11",
doi = "10.1111/bph.14905",
language = "English",
journal = "British Journal of Pharmacology",
issn = "0007-1188",

}

TY - JOUR

T1 - FK506 regulates IP3 evoked Ca2+ release independently of FKBP in endothelial cells

AU - Buckley, Charlotte

AU - Wilson, Calum

AU - McCarron, John G.

PY - 2019/10/11

Y1 - 2019/10/11

N2 - 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 ApproachWe 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 ResultsWhile 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.

AB - 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 ApproachWe 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 ResultsWhile 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.

KW - vascular

KW - endothelium

KW - calcium

KW - FKBP

KW - FK506

KW - rapamycin

KW - okadaic acid

KW - cypermethrin

KW - inositol 1,4,5‐trisphosphate (IP3)

KW - ryanodine receptors

KW - calcineurin

UR - https://bpspubs.onlinelibrary.wiley.com/journal/14765381

U2 - 10.1111/bph.14905

DO - 10.1111/bph.14905

M3 - Article

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -