RRC ID 32472
著者 Gao S, Sandstrom DJ, Smith HE, High B, Marsh JW, Nash HA.
タイトル Drosophila ryanodine receptors mediate general anesthesia by halothane.
ジャーナル Anesthesiology
Abstract BACKGROUND:Although in vitro studies have identified numerous possible targets, the molecules that mediate the in vivo effects of volatile anesthetics remain largely unknown. The mammalian ryanodine receptor (Ryr) is a known halothane target, and the authors hypothesized that it has a central role in anesthesia.
METHODS:Gene function of the Drosophila Ryr (dRyr) was manipulated in the whole body or in specific tissues using a collection of mutants and transgenes, and responses to halothane were measured with a reactive climbing assay. Cellular responses to halothane were studied using Ca imaging and patch clamp electrophysiology.
RESULTS:Halothane potency strongly correlates with dRyr gene copy number, and missense mutations in regions known to be functionally important in the mammalian Ryrs gene cause dominant hypersensitivity. Tissue-specific manipulation of dRyr shows that expression in neurons and glia, but not muscle, mediates halothane sensitivity. In cultured cells, halothane-induced Ca efflux is strictly dRyr-dependent, suggesting a close interaction between halothane and dRyr. Ca imaging and electrophysiology of Drosophila central neurons reveal halothane-induced Ca flux that is altered in dRyr mutants and correlates with strong hyperpolarization.
CONCLUSIONS:In Drosophila, neurally expressed dRyr mediates a substantial proportion of the anesthetic effects of halothane in vivo, is potently activated by halothane in vitro, and activates an inhibitory conductance. The authors' results provide support for Ryr as an important mediator of immobilization by volatile anesthetics.
巻・号 118(3)
ページ 587-601
公開日 2013-3-1
DOI 10.1097/ALN.0b013e31827e52c6
PMID 23254148
PMC PMC3580016
MeSH Amino Acid Sequence Anesthesia, General* Anesthetics, Inhalation / pharmacology* Animals Cell Line Drosophila melanogaster Halothane / pharmacology* Immobilization / methods Male Molecular Sequence Data Point Mutation / drug effects Point Mutation / physiology Ryanodine Receptor Calcium Release Channel / biosynthesis Ryanodine Receptor Calcium Release Channel / genetics Ryanodine Receptor Calcium Release Channel / physiology*
IF 7.067
引用数 8
WOS 分野 ANESTHESIOLOGY
リソース情報
ショウジョウバエ DGRC#202537 10844R-3