論文 - 詳細
| RRC ID | 45102 |
|---|---|
| 著者 | Joseph JD, Peng Y, Mak DO, Cheung KH, Vais H, Foskett JK, Wei H. |
| タイトル | General anesthetic isoflurane modulates inositol 1,4,5-trisphosphate receptor calcium channel opening. |
| ジャーナル | Anesthesiology |
| Abstract |
BACKGROUND:Pharmacological evidence suggests that inhalational general anesthetics induce neurodegeneration in vitro and in vivo through overactivation of inositol trisphosphate receptor (InsP3R) Ca-release channels, but it is not clear whether these effects are due to direct modulation of channel activity by the anesthetics. METHODS:Using single-channel patch clamp electrophysiology, the authors examined the gating of rat recombinant type 3 InsP3R (InsP3R-3) Ca-release channels in isolated nuclei (N = 3 to 15) from chicken lymphocytes modulated by isoflurane at clinically relevant concentrations in the absence and presence of physiological levels of the agonist inositol 1,4,5-trisphosphate (InsP3). The authors also examined the effects of isoflurane on InsP3R-mediated Ca release from the endoplasmic reticulum and changes in intracellular Ca concentration ([Ca]i). RESULTS:Clinically relevant concentrations (approximately 1 minimal alveolar concentration) of the commonly used general anesthetic, isoflurane, activated InsP3R-3 channels with open probability similar to channels activated by 1 µM InsP3 (Po ≈ 0.2). This isoflurane modulation of InsP3R-3 Po depended biphasically on [Ca]i. Combination of isoflurane with subsaturating levels of InsP3 in patch pipettes resulted in at least two-fold augmentations of InsP3R-3 channel Po compared with InsP3 alone. These effects were not noted in the presence of saturating [InsP3]. Application of isoflurane to DT40 cells resulted in a 30% amplification of InsP3R-mediated [Ca]i oscillations, whereas InsP3-induced increase in [Ca]i and cleaved caspase-3 activity were enhanced by approximately 2.5-fold. CONCLUSION:These results suggest that the InsP3R may be a direct molecular target of isoflurane and plays a role in the mechanisms of anesthetic-mediated pharmacological or neurotoxic effects. |
| 巻・号 | 121(3) |
| ページ | 528-37 |
| 公開日 | 2014-9-1 |
| DOI | 10.1097/ALN.0000000000000316 |
| PMID | 24878495 |
| PMC | PMC4281525 |
| MeSH | Anesthetics, Inhalation / pharmacology* Animals Apoptosis / drug effects Calcium / metabolism Calcium Channels / drug effects* Calcium Channels / physiology Calcium Signaling / drug effects Cells, Cultured Chickens Inositol 1,4,5-Trisphosphate Receptors / drug effects* Inositol 1,4,5-Trisphosphate Receptors / physiology Isoflurane / pharmacology* Rats |
| IF | 7.067 |
| 引用数 | 20 |
| WOS 分野 | ANESTHESIOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | IP3R^(-) DT40(RCB1467) |