Role of CRF receptor signaling in stress vulnerability, anxiety, and depression.
Role of CRF receptor signaling in stress vulnerability, anxiety, and depression.
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DOI：
10.1111/j.1749-6632.2009.05011.x
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发表时间：
2009-10
影响因子：
5.2
通讯作者：
Dautzenberg FM
中科院分区：
文献类型：
--
作者：
Hauger RL;Risbrough V;Oakley RH;Olivares-Reyes JA;Dautzenberg FM
焦虑和抑郁障碍患者中枢性促肾上腺皮质激素释放因子(CRF)系统和CRF相关单核苷酸多态(SNPs)的标志物已被发现。现在，设计更有效的拮抗剂可能会受到数据的指导，这些数据表明，小分子与跨膜结构域结合。具体地说，CRF1受体拮抗剂已被开发为抗焦虑和抗抑郁的新疗法。由于在高浓度激动剂存在下，CRF1受体被G蛋白偶联受体激酶和β-arrestin机制迅速脱敏，单靠突触CRF的高分泌可能不足以解释应激诱导的情感性病理生理学中过度的中枢性CRF神经传递。除了脱敏受体功能外，GRK磷酸化和β-arrestin结合还可以使G蛋白偶联受体选择性地通过细胞外信号调节激酶/丝裂原活化蛋白激酶或不依赖于G蛋白的Akt通路传递信号。此外，通过ERK-MAPK通路的EPAC依赖的CRF1受体信号也被发现增强了脑源性神经营养因子(BDNF)刺激的TrkB信号。因此，GRK和β-arrestin功能的遗传或获得性异常可能参与了应激性焦虑和抑郁的病理生理过程。
Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF-related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF1 receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF1 receptors become rapidly desensitized by G protein-coupled receptor kinase (GRK) and β-arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress-induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and β-arrestin binding can shift a G protein-coupled receptor (GPCR) to signal selectively via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) or Akt pathways independent of G proteins. Also, Epac-dependent CRF1 receptor signaling via the ERK-MAPK pathway has been found to potentiate brain-derived neurotrophic factor (BDNF)-stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and β-arrestin function may be involved in the pathophysiology of stress-induced anxiety and depression.
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影响因子：
--
作者：
Dwivedi, Yogesh;Mondal, Amal C.;Pandey, Ghanshyam N.
通讯作者：
Pandey, Ghanshyam N.
影响因子：
2.9
作者：
Dieterich, KD;Grigoriadis, DE;DeSouza, EB
通讯作者：
DeSouza, EB
DOI：
10.1016/s0006-8993(01)03046-3
发表时间：
2001-11-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Erdtmann-Vourliotis, M;Mayer, P;Höllt, V
通讯作者：
Höllt, V
影响因子：
4.8
作者：
Deak, T;Nguyen, KT;Gold, PW
通讯作者：
Gold, PW
影响因子：
17.7
作者：
Avissar, S;Matuzany-Ruban, A;Schreiber, G
通讯作者：
Schreiber, G