Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications.
Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications.
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DOI：
10.1002/ajmg.b.32023
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发表时间：
2012-03
影响因子：
2.8
通讯作者：
Miller, Gregory M.
中科院分区：
文献类型：
--
作者：
Chen, Guo-Lin;Miller, Gregory M.
5-羟色胺（5-HT）通过与下丘脑-垂体-肾上腺（HPA）轴和神经元交感神经系统（SNS）相互作用调节应激反应。色氨酸羟化酶（TPH）是5-羟色胺生物合成中的限速酶，最近发现的第二种神经元特异性TPH异构体（TPH2）开辟了一个新的研究领域。虽然TPH2基因变异与许多行为特征和疾病有关，但对TPH2基因表达的发现不仅加强了，而且为长期认识但尚未完全理解的5- ht -应激相互作用提供了新的见解。本文就TPH2表达调控及其与应激反应的关系及临床意义等方面的研究进展进行综述。特别是，根据恒河猴TPH2遗传学研究结果及相关文献，我们提出：1)肾上腺皮质醇分泌激活后，皮质醇激增诱导TPH2表达和5-HT从头合成；2)诱导的5-HT通过视交叉上核(SCN)-神经网络-肾上腺系统调节肾上腺对ACTH的敏感性，进而抑制皮质醇分泌，从而反馈抑制皮质醇的产生；3)基础TPH2表达或5-HT合成，以及早期生活经历，主要通过激素HPA轴影响基础皮质醇；4) TPH2的5′-和3′-调控多态性可能会对应激反应产生不同的影响，可能是由于它们在基因表达调控中的作用不同。我们对TPH2表达调控的不断了解不仅有助于我们更好地理解5- ht -应激相互作用和神经精神疾病的病理生理，而且为应激相关疾病的治疗提供了新的策略。
Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: 1) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; 2) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; 3) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and 4) 5′- and 3′-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases.
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影响因子：
3.3
作者：
Bonkale, W. L.;Austin, M. C.
通讯作者：
Austin, M. C.
DOI：
10.1073/pnas.0810793106
发表时间：
2009-06-23
影响因子：
11.1
作者：
Alenina, Natalia;Kikic, Dana;Bader, Michael
通讯作者：
Bader, Michael
影响因子：
4
作者：
Abumaria, Nashat;Ribic, Adema;Fluegge, Gabriele
通讯作者：
Fluegge, Gabriele
影响因子：
5.3
作者：
Cervo, L;Canetta, A;Invernizzi, RW
通讯作者：
Invernizzi, RW
影响因子：
12.7
作者：
Bromberger, JT;Meyer, PM;Sutton-Tyrrell, K
通讯作者：
Sutton-Tyrrell, K