Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation
Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation
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Trpm1 点突变导致的去极化双极细胞功能障碍
DOI：
10.1152/jn.00137.2012
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发表时间：
2012-11-01
影响因子：
2.5
通讯作者：
Gregg, Ronald G.
中科院分区：
文献类型：
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作者：
Peachey, Neal S.;Pearring, Jillian N.;Gregg, Ronald G.
皮奇NS，皮林JN，Bojang P Jr，Hirschtritt ME，斯特吉尔-Short G，Ray TA，Furukawa T，小池C，Goldberg AF，沈勇，McCall MA，Nawy S，Nishina PM，Gregg RG。Trpm1点突变导致的去极化双极细胞功能障碍。神经生理学杂志108：2442-2451,2012。2012年8月15日首次发表；doi：10.1152/jn.00137.2012。-在患有常染色体隐性遗传性完全性先天性静止性夜盲(CCSNB)的人类中发现TRPM1突变。Trpm1(-/-)小鼠是该疾病的重要动物模型。在这里，我们报告了一种新的小鼠突变体TVRM27，它是在化学诱变筛选中发现的。TVrm27的视网膜电信号(ERG)表型的遗传图谱将突变定位于包括Trpm1的染色体区域。对Trpm1(-/-)小鼠的互补测试证实了Trpm1的突变。测序证实了外显子23的核苷酸变化，将多孔区内高度保守的丙氨酸转化为苏氨酸(A1068T页)。与先前对Trpm1(-/-)小鼠的研究一致，Trpm1(TVRM27/TVRM27)视网膜没有观察到解剖学上的变化。与Trpm1(-/-)不同的是，去极化双极细胞(DBCS)的树突状尖端保留了TRPM1的表达。Trpm1(+/-)杂合子小鼠的ERGb波幅与野生型相当，而Trpm1(+/twrm27)小鼠的ERGb波幅降低了32%。在全细胞记录中，Trpm1(+/Athrm27)DBCS对LY341495或辣椒素的反应也明显降低。这些数据表明，P.A1068T突变体TRPM1对TRPM1通道功能起显性负性作用。此外，这些数据表明，DBC树突状顶端的功能TRPM1通道的数量是决定DBC反应幅度的关键因素。Trpm1突变体将有助于阐明TRPM1在DBC信号转导中的作用，确定Trpm1突变如何影响中枢视觉加工，并用于评估cCSNB的实验治疗。
Peachey NS, Pearring JN, Bojang P Jr, Hirschtritt ME, Sturgill-Short G, Ray TA, Furukawa T, Koike C, Goldberg AF, Shen Y, McCall MA, Nawy S, Nishina PM, Gregg RG. Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. J Neurophysiol 108: 2442-2451, 2012. First published August 15, 2012; doi:10.1152/jn.00137.2012.-Mutations in TRPM1 are found in humans with an autosomal recessive form of complete congenital stationary night blindness (cCSNB). The Trpm1(-/-) mouse has been an important animal model for this condition. Here we report a new mouse mutant, tvrm27, identified in a chemical mutagenesis screen. Genetic mapping of the no b-wave electroretinogram (ERG) phenotype of tvrm27 localized the mutation to a chromosomal region that included Trpm1. Complementation testing with Trpm1(-/-) mice confirmed a mutation in Trpm1. Sequencing identified a nucleotide change in exon 23, converting a highly conserved alanine within the pore domain to threonine (p. A1068T). Consistent with prior studies of Trpm1(-/-) mice, no anatomical changes were noted in the Trpm1(tvrm27/tvrm27) retina. The Trpm1(tvrm27/tvrm27) phenotype is distinguished from that of Trpm1(-/-) by the retention of TRPM1 expression on the dendritic tips of depolarizing bipolar cells (DBCs). While ERG b-wave amplitudes of Trpm1(+/-) heterozygotes are comparable to wild type, those of Trpm1(+/tvrm27) mice are reduced by 32%. A similar reduction in the response of Trpm1(+/tvrm27) DBCs to LY341495 or capsaicin is evident in whole cell recordings. These data indicate that the p. A1068T mutant TRPM1 acts as a dominant negative with respect to TRPM1 channel function. Furthermore, these data indicate that the number of functional TRPM1 channels at the DBC dendritic tips is a key factor in defining DBC response amplitude. The Trpm1(tvrm27/tvrm27) mutant will be useful for elucidating the role of TRPM1 in DBC signal transduction, for determining how Trpm1 mutations impact central visual processing, and for evaluating experimental therapies for cCSNB.