Mazella Jean, Borsotto Marc, Heurteaux Catherine
CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, Valbonne, France.
Front Pharmacol. 2019 Jan 8;9:1541. doi: 10.3389/fphar.2018.01541. eCollection 2018.
The molecular identification of sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble sortilin. Therefore, sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analog spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of sortilin and the sortilin-derived PE have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble sortilin and of sortilin-derived PE as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review.
通过三种不同的生化方法对sortilin（也称为神经降压素受体-3）进行分子鉴定，已经预测到该蛋白参与了众多生物学和细胞功能。第一个重要发现是，sortilin最初作为前体合成，在高尔基体晚期被蛋白转化酶弗林蛋白酶切割后转化为成熟蛋白。这种成熟过程导致形成一个44个氨基酸的肽段，即前肽（PE）。成熟的sortilin到达质膜时该肽段的释放情况仍有待证实。sortilin还被证明可被基质金属蛋白酶切割，释放出一个被鉴定为可溶性sortilin的大细胞外片段。因此，sortilin已被证明能与多种蛋白质和受体相互作用，证实了其在将细胞成分分选至质膜和/或溶酶体途径中的作用。有趣的是，sortilin与双孔域钾通道TREK-1发生物理相互作用，并且PE及其合成类似物spadin能够阻断TREK-1的激活，突出了它们在抑郁症病理中的作用。本综述描述了导致这些结果的研究进展，以及如何在人血清中检测到sortilin的可溶性形式和sortilin衍生的PE，并且其水平在重度抑郁症（MDD）患者中受到影响。本综述考虑并讨论了spadin作为抗抑郁药的用途，以及可溶性sortilin和sortilin衍生的PE在抑郁症病情陈述和/或病理缓解期间作为潜在生物标志物的进一步作用。
