Characterization of intracellular calcium mobilization induced by remimazolam, a newly approved intravenous anesthetic
| Autor: | Tomoaki Urabe, Hirotsugu Miyoshi, Soshi Narasaki, Yuhki Yanase, Kazue Uchida, Soma Noguchi, Michihiro Hide, Yasuo M. Tsutsumi, Norio Sakai |
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| Rok vydání: | 2021 |
| Předmět: |
Transmembrane Receptors
Imaging Techniques Science General Anesthesia Neuroimaging Endoplasmic Reticulum Research and Analysis Methods Biochemistry Dantrolene Intracellular Receptors Cell Line Benzodiazepines Alkaloids Cell Signaling Drug Therapy Anesthesiology Caffeine Fluorescence Imaging Human Umbilical Vein Endothelial Cells Medicine and Health Sciences Humans Inositol 1 4 5-Trisphosphate Receptors Pain Management Anesthesia Calcium Signaling Anesthetics Pharmacology Multidisciplinary Pharmaceutics Chemical Compounds Biology and Life Sciences Proteins Drugs Ryanodine Receptor Calcium Release Channel Cell Biology Calcium Imaging Chemistry Physical Sciences Medicine Thapsigargin Calcium G Protein Coupled Receptors Signal Transduction Research Article Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 17, Iss 2 (2022) |
| ISSN: | 1932-6203 |
| Popis: | Many anesthetics, including Propofol, have been reported to induce elevation of intracellular calcium, and we were interested to investigate the possible contribution of calcium elevation to the mechanism of the newly approved remimazolam actions. Remimazolam is an intravenous anesthetic first approved in Japan in July 2020, and is thought to exert its anesthetic actions via γ-aminobutyric acid A (GABAA) receptors; however, the precise mechanisms of how remimazolam elevates intracellular calcium levels remains unclear. We examined the remimazolam-induced elevation of intracellular calcium using SHSY-5Y neuroblastoma cells, COS-7 cells, HEK293 cells, HeLa cells, and human umbilical vein endothelial cells (HUVECs) loaded with fluorescent dyes for live imaging. We confirmed that high concentrations of remimazolam (greater than 300 μM) elevated intracellular calcium in a dose-dependent manner in these cells tested. This phenomenon was not influenced by elimination of extracellular calcium. The calcium elevation was abolished when intracellular or intraendoplasmic reticulum (ER) calcium was depleted by BAPTA-AM or thapsigargin, respectively, suggesting that calcium was mobilized from the ER. Inhibitors of G-protein coupled receptors (GPCRs)-mediated signals, including U-73122, a phospholipase C (PLC) inhibitor and xestospongin C, an inositol 1,4,5-triphosphate receptors (IP3R) antagonist, significantly suppressed remimazolam-induced calcium elevation, whereas dantrolene, a ryanodine receptor antagonist, did not influence remimazolam-induced calcium elevation. Meanwhile, live imaging of ER during remimazolam stimulation using ER-tracker showed no morphological changes. These results suggest that high doses of remimazolam increased intracellular calcium concentration in a dose-dependent manner in each cell tested, which was predicted to be caused by calcium mobilization from the ER. In addition, our studies using various inhibitors revealed that this calcium elevation might be mediated by the GPCRs-IP3 pathway. However, further studies are required to identify which type of GPCRs is involved. |
| Databáze: | OpenAIRE |
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