Simvastatin activates single skeletal RyR1
channels but exerts more complex regulation
of the cardiac RyR2 isoform
Rebecca Sitsapesan, Department of Pharmacology, University of Oxford, Mansﬁeld Road, Oxford, OX1 3QT, UK.
12 April 2017;
23 November 2017;
13 December 2017
* , Chris Lindsay
* , Sabine Lotteau
, Zhaokang Yang
, Emma Steer
, Katja Witschas
Abigail D Wilson
, Angela J Russell
, Derek Steele
, Sarah Calaghan
Department of Pharmacology, University of Oxford, Oxford, UK,
School of Biomedical Sciences, University of Leeds, Leeds, UK, and
Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK
*These authors contributed equally to this work.
BACKGROUND AND PURPOSE
Statins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by
inhibiting 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. Although effective at preventing cardiovascular disease, statin use
is associated with muscle weakness, myopathies and, occasionally, fatal rhabdomyolysis. As simvastatin, a commonly prescribed
statin, promotes Ca
release from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin directly activates skeletal
(RyR1) and cardiac (RyR2) ryanodine receptors.
RyR1 and RyR2 single-channel behaviour was investigated after incorporation of sheep cardiac or mouse skeletal SR into planar
phospholipid bilayers under voltage-clamp conditions. LC-MS was used to monitor the kinetics of interconversion of simvastatin
between hydroxy-acid and lactone forms during these experiments. Cardiac and skeletal myocytes were permeabilised to
examine simvastatin modulation of SR Ca
Hydroxy acid simvastatin (active at HMG-CoA reductase) signiﬁcantly and reversibly increased RyR1 open probability (Po) and
shifted the distribution of Ca
spark frequency towards higher values in skeletal ﬁbres. In contrast, simvastatin reduced RyR2 Po
and shifted the distribution of spark frequency towards lower values in ventricular cardiomyocytes. The lactone pro-drug form of
simvastatin (inactive at HMG-CoA reductase) also activated RyR1, suggesting that the HMG-CoA inhibitor pharmacophore was
not responsible for RyR1 activation.
CONCLUSION AND IMPLICATIONS
Simvastatin interacts with RyR1 to increase SR Ca
release and thus may contribute to its reported adverse effects on skeletal
muscle. The ability of low concentrations of simvastatin to reduce RyR2 Po may also protect against Ca
and sudden cardiac death.
AF, atrial ﬁbrillation; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; CCD, central core disease; FDB, ﬂexor
digitorum brevis; HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; Log D, partition coefﬁcient; MH, malignant hyperthermia;
Po, open probability; RyR, ryanodine receptor; Sim-H, simvastatin hydroxy acid; Sim-L, simvastatin lactone; SR, sarco-
plasmic reticulum; Trans,luminal
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-
vided the original work is properly cited.
British Journal of
British Journal of Pharmacology (2018) 175 938–952 938
DOI:10.1111/bph.14136 © 2017 The Authors. British Journal of Pharmacology
published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.