The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol.
The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol.
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DOI：
10.1097/fpc.0b013e32833d8c20
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发表时间：
2010-09
影响因子：
2.6
通讯作者：
Johnson TE
中科院分区：
文献类型：
--
作者：
Downing C;Marks MJ;Larson C;Johnson TE
近交长睡眠和短睡眠小鼠（ILS 和 ISS）经过选择性繁殖，以对乙醇的镇静作用具有不同的敏感性。来自这些祖细胞的小鼠品系已被用来鉴定介导乙醇引起的翻正反射丧失（LORE）的几个数量性状位点（QTL）。本研究调查了 mGluR5 作为 Lore7 的候选基因，Lore7 是介导 LORE 敏感性差异的 QTL。我们使用基因敲除小鼠、定量互补试验、mGluR5 药理拮抗作用、实时定量 PCR、放射性配体结合、DNA 测序和生物信息学来研究 mGluR5 在乙醇诱导镇静中的作用。 mGluR5 敲除小鼠的 LORE 持续时间明显长于野生型对照小鼠。给予 mGluR5 拮抗剂 2-甲基-6-(苯乙基)-吡啶 (MPEP) 对 ILS 和 ISS 小鼠的 LORE 有不同的影响。定量互补测试也支持 mGluR5 介导 LORE。 mGluR5 中的两个内含子单核苷酸多态性与源自 ILS 和 ISS (LXS RI) 杂交的重组近交小鼠中的 LORE 高度相关。在不同脑区的 ILS 和 ISS 之间观察到 mGluR5 mRNA 水平和受体密度的差异。最后，来自 WebQTL 的数据表明 mGluR5 表达与 LXS RI 中的几种 LORE 表型高度相关。总而言之，这些数据提供了令人信服的证据，表明 mGluR5 介导对乙醇镇静作用的不同敏感性。来自人类文献的研究也确定了 MGLUR5 是乙醇敏感性的潜在候选基因。
Inbred Long-Sleep and Short-Sleep mice (ILS and ISS) were selectively bred for differential sensitivity to the sedative effects of ethanol. Lines of mice derived from these progenitors have been used to identify several Quantitative Trait Loci (QTLs) mediating Loss Of the Righting reflex due to Ethanol (LORE). The present study investigated mGluR5 as a candidate gene underlying Lore7, a QTL mediating differential LORE sensitivity. We used knockout mice, a quantitative complementation test, pharmacological antagonism of mGluR5, real-time quantitative PCR, radioligand binding, DNA sequencing and bioinformatics to examine the role of mGluR5 in ethanol-induced sedation. mGluR5 knockout mice had a significantly longer LORE duration than wild-type controls. Administration of the mGluR5 antagonist 2-methyl-6-(phenylethyl)-pyridine (MPEP) had differential effects on LORE in ILS and ISS mice. A quantitative complementation test also supported mGluR5 mediating LORE. Two intronic single-nucleotide polymorphisms in mGluR5 were highly correlated with LORE in recombinant inbred mice derived from a cross between ILS and ISS (LXS RIs). Differences in mGluR5 mRNA level and receptor density were observed between ILS and ISS in distinct brain regions. Finally, data from WebQTL showed that mGluR5 expression was highly correlated with several LORE phenotypes in the LXS RIs. Taken together, this data provides convincing evidence that mGluR5 mediates differential sensitivity to the sedative effects of ethanol. Studies from the human literature have also identified MGLUR5 as a potential candidate gene for ethanol sensitivity.