A putative cation channel and its novel regulator: Cross-species conservation of effects on general anesthesia
A putative cation channel and its novel regulator: Cross-species conservation of effects on general anesthesia
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DOI：
10.1016/j.cub.2007.02.037
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发表时间：
2007-04-03
期刊：
影响因子：
9.2
通讯作者：
Nash, Howard A.
中科院分区：
文献类型：
--
作者：
Humphrey, John A.;Hamming, Kevin S.;Nash, Howard A.
像氟烷和安氟醚这样的挥发性麻醉剂引起了临床医生和神经学家的兴趣，因为它们有能力优先扰乱构成意识状态的高级功能。全。挥发物曾经被认为作用相同；如果是这样的话，它们应该同样受到基因变异的影响。然而，据报道，两个不同的基因突变，一个在线虫中，一个在果蝇中，对氟烷的反应产生的影响比安氟醚大得多[1，2]。为了弄清这种麻醉信号是外来的还是基本的，我们已经确定了每个基因的同源基因，并确定了每个物种中的突变表型。苍蝇基因窄腹(NA)编码一个可能的离子通道，该通道的序列使其属于一个独特的家族；线虫基因UNC-79在这里被鉴定为编码一个缺乏明显基序的大型胞浆蛋白。在线虫病中，使两个NA同源基因失活的突变产生UNC-79表型；在果蝇中，使UNC-79同源基因失活的突变产生安娜表型。在每个生物体中，对双突变的研究将这些基因置于相同的途径中，生物化学研究表明，UNC-79家族的蛋白质通过转录后机制控制NA蛋白的水平。因此，麻醉剂的签名反映了NA同源基因在进化上的保守作用，暗示它与药物作用密切相关。
Volatile anesthetics like halothane and enflurane are of interest to clinicians and neuroscientists because of their ability to preferentially disrupt higher functions that make up the conscious state. All. volatiles were once thought to act identically; if so, they should be affected equally by genetic variants. However, mutations in two distinct genes, one in Caenorhabditis and one in Drosophila, have been reported to produce much larger effects on the response to halothane than enflurane [1, 2]. To see whether this anesthesia signature is adventitious or fundamental, we have identified orthologs of each gene and determined the mutant phenotype within each species. The fly gene, narrow abdomen (na), encodes a putative ion channel whose sequence places it in a unique family; the nematode gene, unc-79, is identified here as encoding a large cytosolic protein that lacks obvious motifs. In Caenorhabditis, mutations that inactivate both of the na orthologs produce an Unc-79 phenotype; in Drosophila, mutations that inactivate the unc-79 orthologs produce an na phenotype. In each organism, studies of double mutants place the genes in the same pathway, and biochemical studies show that proteins of the UNC-79 family control NA protein levels by a posttranscriptional mechanism. Thus, the anesthetic signature reflects an evolutionarily conserved role for the na orthologs, implying its intimate involvement in drug action.