Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: New molecular targets
Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: New molecular targets
复制标题
DOI：
10.2174/187152706777950684
复制
发表时间：
2006-08-01
影响因子：
3
通讯作者：
Dautzenberg, Frank M.
中科院分区：
文献类型：
--
作者：
Hauger, Richard L.;Risbrough, Victoria;Dautzenberg, Frank M.
促肾上腺皮质激素释放因子（CRF）及其相关的尿皮质素肽通过激活中枢神经系统和垂体前叶的CRF 1或CRF 2受体介导对厌恶性刺激的行为、认知、自主神经、神经内分泌和免疫反应。在焦虑、应激和抑郁障碍患者亚群中，已确定了中枢CRF系统过度活跃的标志物，包括CRF分泌过多和下丘脑-垂体-肾上腺轴功能异常。由于CRF受体在高浓度激动剂存在下迅速脱敏，因此仅CRF分泌过多可能不足以解释在这些患者中观察到的CRF神经传递增强。伴随着严格控制CRF受体信号传导的幅度和持续时间的机制的失调也可能导致这种现象。虽然CRF 1受体介导了许多焦虑和抑郁样行为以及HPA轴应激反应，但CRF 2受体的功能目前还不清楚。一种假说认为，CRF 1受体激活启动恐惧和焦虑样反应，而CRF 2受体激活通过抵消CRF受体信号传导的厌恶效应来重建稳态。所有备择假设假定CRF 1和CRF 2受体有助于相反的防御模式，CRF 2受体介导由可逃避的压力源引发的主动防御反应，CRF 2受体介导由不可避免的，不可控制的压力源诱导的焦虑和抑郁样反应。CRF 1受体拮抗剂正被开发为情感和应激障碍的新型治疗方法。如果证实CRF 2受体对焦虑和抑郁有重要作用，则开发小分子CRF 2受体拮抗剂将在治疗上有用。
Corticotropin-releasing factor (CRF) and the related urocortin peptides mediate behavioral, cognitive, autonomic, neuroendocrine and immunologic responses to aversive stimuli by activating CRF1 or CRF2 receptors in the central nervous system and anterior pituitary. Markers of hyperactive central CRF systems, including CRF hypersecretion and abnormal hypothalamic-pituitary-adrenal axis functioning, have been identified in subpopulations of patients with anxiety, stress and depressive disorders. Because CRF receptors are rapidly desensitized in the presence of high agonist concentrations, CRF hypersecretion alone may be insufficient to account for the enhanced CRF neurotransmission observed in these patients. Concomitant dysregulation of mechanisms stringently controlling magnitude and duration of CRF receptor signaling also may contribute to this phenomenon. While it is well established that the CRF1 receptor mediates many anxiety- and depression-like behaviors as well as HPA axis stress responses, CRF2 receptor functions are not well understood at present. One hypothesis holds that CRF1 receptor activation initiates fear and anxiety-like responses, while CRF2 receptor activation re-establishes homeostasis by counteracting the aversive effects of CRF, receptor signaling. All alternative hypothesis,posits that CRF1 and CRF2 receptors contribute to opposite defensive modes, with CRF2 receptors mediating active defensive responses triggered by escapable stressors, and CRF2 receptors mediating anxiety- and depression-like responses induced by inescapable, uncontrollable stressors. CRF1 receptor antagonists are being developed as novel treatments for affective and stress disorders. If it is confirmed that the CRF2 receptor contributes importantly to anxiety and depression, the development of small molecule CRF, receptor antagonists would be therapeutically useful.