4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.
4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.
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DOI：
10.1186/1471-2377-12-104
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发表时间：
2012-09-24
期刊：
影响因子：
2.6
通讯作者：
Ahrens J
中科院分区：
文献类型：
--
作者：
de la Roche J;Leuwer M;Krampfl K;Haeseler G;Dengler R;Buchholz V;Ahrens J
哺乳动物的遗传性神经功能亢进可归因于士的宁敏感的甘氨酸受体的各种突变。惊厥病的临床症状主要发生在新生儿，导致惊厥性高张力和对意想不到的轻微刺激的夸大惊恐反应。其中，对士的宁敏感的甘氨酸受体α1-亚单位的R271Q和R271L点突变显示甘氨酸敏感性降低，并导致临床症状亢进。卤化作用已被证明是酚类化合物积极调节甘氨酸受体功能的关键结构决定因素。这项体外研究的目的是研究4-氯丙酚(4-氯-2，6-二甲基苯酚)对四种甘氨酸受体突变的影响。在HEK 293细胞中表达甘氨酸受体亚基，并采用全细胞膜片钳技术进行实验。4-氯丙酚在野生型受体的低亚纳摩尔浓度范围(EC50值为0.08±0.02 nM)和突变的微摩尔浓度范围内(R271Q、L、K和S267I的EC50值分别为1.3±0.6μM、0.1±0.2μM、6.0±2.3μM和55±28μM)具有正的变构调节作用。4-氯异丙酚可能是惊厥病模型中激活突变甘氨酸受体的有效化合物。
The mammalian neurological disorder hereditary hyperekplexia can be attributed to various mutations of strychnine sensitive glycine receptors. The clinical symptoms of “startle disease” predominantly occur in the newborn leading to convulsive hypertonia and an exaggerated startle response to unexpected mild stimuli. Amongst others, point mutations R271Q and R271L in the α1-subunit of strychnine sensitive glycine receptors show reduced glycine sensitivity and cause the clinical symptoms of hyperekplexia. Halogenation has been shown to be a crucial structural determinant for the potency of a phenolic compound to positively modulate glycine receptor function. The aim of this in vitro study was to characterize the effects of 4-chloropropofol (4-chloro-2,6-dimethylphenol) at four glycine receptor mutations. Glycine receptor subunits were expressed in HEK 293 cells and experiments were performed using the whole-cell patch-clamp technique. 4-chloropropofol exerted a positive allosteric modulatory effect in a low sub-nanomolar concentration range at the wild type receptor (EC50 value of 0.08 ± 0.02 nM) and in a micromolar concentration range at the mutations (1.3 ± 0.6 μM, 0.1 ± 0.2 μM, 6.0 ± 2.3 μM and 55 ± 28 μM for R271Q, L, K and S267I, respectively). 4-chloropropofol might be an effective compound for the activation of mutated glycine receptors in experimental models of startle disease.
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DOI：
10.1085/jgp.20028530
发表时间：
2002-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Beato M;Groot-Kormelink PJ;Colquhoun D;Sivilotti LG
通讯作者：
Sivilotti LG
影响因子：
16.2
作者：
Grudzinska, J;Schemm, R;Laube, B
通讯作者：
Laube, B
影响因子：
5.2
作者：
Becker, Kristina;Breitinger, Hans-Georg;Becker, Cord-Michael
通讯作者：
Becker, Cord-Michael
影响因子：
4.8
作者：
Carland, Jane E.;Cooper, Michelle A.;Moorhouse, Andrew J.
通讯作者：
Moorhouse, Andrew J.
DOI：
10.1073/pnas.82.2.488
发表时间：
1985-01-01
影响因子：
11.1
作者：
KUNKEL, TA
通讯作者：
KUNKEL, TA