Kasture Ameya, Stockner Thomas, Freissmuth Michael, Sucic Sonja
Institute of Pharmacology, Center of Physiology and Pharmacology and Gaston H. Glock Research Laboratories for Exploratory Drug Development, Medical University of Vienna, Austria.
Institute of Pharmacology, Center of Physiology and Pharmacology and Gaston H. Glock Research Laboratories for Exploratory Drug Development, Medical University of Vienna, Austria.
Int J Biochem Cell Biol. 2017 Nov;92:1-5. doi: 10.1016/j.biocel.2017.09.004. Epub 2017 Sep 7.
The key role of monoamine transporters is to take up neurotransmitters from the synaptic cleft and rapidly terminate neurotransmission. Monoamine transporters begin their journey by folding in the endoplasmic reticulum. Upon achieving their natively-folded state, the oligomerized transporters engage the coat protein complex II machinery and exit the endoplasmic reticulum compartment in a concentrative fashion. The transporters are subsequently sorted in the endoplasmic reticulum-Golgi intermediate complex and the Golgi apparatus, prior to reaching their pivotal site of action at the plasma membrane. Stringent quality-control mechanisms ensure that only the correctly-folded protein cargo departs the endoplasmic reticulum. Genetic point mutations in the coding sequences of monoamine transporters can trigger severe physiologic deficiencies by inducing folding defects. Protein misfolding precludes the delivery of functional monoamine transporters to the cell surface. Chemical- and/or pharmacological-chaperone molecules, which facilitate folding, have proven effective in restoring the activity of several misfolded pathological variants of monoamine transporters.
单胺转运体的关键作用是从突触间隙摄取神经递质并迅速终止神经传递。单胺转运体在内质网中折叠开始其行程。达到天然折叠状态后，寡聚化的转运体与衣被蛋白复合物II机制结合，并以浓缩方式离开内质网区室。转运体随后在内质网-高尔基体中间复合物和高尔基体中进行分选，然后到达其在质膜上的关键作用位点。严格的质量控制机制确保只有正确折叠的蛋白质货物离开内质网。单胺转运体编码序列中的基因点突变可通过诱导折叠缺陷引发严重的生理缺陷。蛋白质错误折叠会阻止功能性单胺转运体转运到细胞表面。已证明促进折叠的化学和/或药理伴侣分子可有效恢复单胺转运体几种错误折叠的病理变体的活性。
