@article { , title = {Simvastatin inhibits L-type Ca2+-channel activity through impairment of mitochondrial function}, abstract = {© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognized "off targets" for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study, we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells because mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca2+ influx via opening of voltage-gated Ca2+ channels (VGCCs). We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption, and ATP-sensitive-K+- channel activity were monitored as markers of mETC activity, respiration, and cellular ATP/ADP ratio respectively; Ca2+ channel activity and Ca2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 approximately 3 mM) and mETC (1 < IC50 < 10 mM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 mM reversed activation of VGCCs by glucose but had no significant effect in the sugar s absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an "off target".}, doi = {10.1093/toxsci/kfz068}, eissn = {1096-0929}, issn = {1096-6080}, issue = {2}, journal = {Toxicological Sciences}, pages = {543–552}, publicationstatus = {Published}, publisher = {Oxford University Press}, url = {https://nottingham-repository.worktribe.com/output/2079523}, volume = {169}, keyword = {Toxicology}, year = {2019}, author = {Curry, Liam and Almukhtar, Hani and Alahmed, Jala and Roberts, Richard and Smith, Paul A} }