Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.
Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.
复制标题
神经递质转运蛋白疾病变异的功能和生化后果：特别强调折叠和运输缺陷。
DOI：
10.1016/j.pharmthera.2020.107785
复制
发表时间：
2021-06
影响因子：
13.5
通讯作者：
Sucic S
中科院分区：
文献类型：
--
作者：
Bhat S;El-Kasaby A;Freissmuth M;Sucic S
神经递质，如γ-氨基丁酸、谷氨酸、乙酰胆碱、甘氨酸和单胺，促进中枢神经系统内的串扰。指定的神经递质转运蛋白（NTTs）既释放神经递质，又从突触间隙摄取神经递质。NTT功能障碍可导致严重的病理生理后果，例如癫痫、智力残疾或帕金森病。NTT的基因点突变最近被认为与各种神经系统疾病的发病有关。这些突变中的一些触发NTT蛋白中的折叠缺陷。正确的折叠是NTT从内质网（ER）输出以及随后运输到其相关作用位点（通常在质膜）的先决条件。最近的研究已经揭示了负责转运蛋白折叠的分子机制中的一些关键特征，例如，热休克蛋白在微调细胞内质网质量控制机制中的作用。了解这些事件的治疗意义从越来越多的报告中显而易见，这些报告将不同的病理条件与NTT错误折叠直接联系起来。例如，多巴胺或GABA的人类转运蛋白的折叠缺陷变体分别导致婴儿帕金森症/肌张力障碍和癫痫。从治疗的角度来看，一些折叠缺陷的NTT可以通过小分子进行功能性拯救，这些小分子被称为化学和药理学伴侣。
Neurotransmitters, such as γ-aminobutyric acid, glutamate, acetyl choline, glycine and the monoamines, facilitate the crosstalk within the central nervous system. The designated neurotransmitter transporters (NTTs) both release and take up neurotransmitters to and from the synaptic cleft. NTT dysfunction can lead to severe pathophysiological consequences, e.g. epilepsy, intellectual disability, or Parkinson’s disease. Genetic point mutations in NTTs have recently been associated with the onset of various neurological disorders. Some of these mutations trigger folding defects in the NTT proteins. Correct folding is a prerequisite for the export of NTTs from the endoplasmic reticulum (ER) and the subsequent trafficking to their pertinent site of action, typically at the plasma membrane. Recent studies have uncovered some of the key features in the molecular machinery responsible for transporter protein folding, e.g., the role of heat shock proteins in fine-tuning the ER quality control mechanisms in cells. The therapeutic significance of understanding these events is apparent from the rising number of reports, which directly link different pathological conditions to NTT misfolding. For instance, folding-deficient variants of the human transporters for dopamine or GABA lead to infantile parkinsonism/dystonia and epilepsy, respectively. From a therapeutic point of view, some folding-deficient NTTs are amenable to functional rescue by small molecules, known as chemical and pharmacological chaperones.
影响因子：
5
作者：
Ennis, Elizabeth A.;Wright, Jane;Retzlaff, Cassandra L.;McManus, Owen B.;Lin, Zhinong;Huang, Xiaofang;Wu, Men;Li, Min;Daniels, J. Scott;Lindsley, Craig W.;Hopkins, Corey R.;Blakely, Randy D.
通讯作者：
Blakely, Randy D.
影响因子：
4.7
作者：
Hahn, Maureen K.;Steele, Angela;Couch, R. Steven;Stein, Mark A.;Krueger, Jessica J.
通讯作者：
Krueger, Jessica J.