De Souza E B
Neurocrine Biosciences Inc., San Diego, CA 92121, USA.
Psychoneuroendocrinology. 1995;20(8):789-819. doi: 10.1016/0306-4530(95)00011-9.
Corticotropin-releasing factor (CRF) plays a major role in coordinating the endocrine, autonomic, behavioral and immune responses to stress through actions in the brain and the periphery. CRF receptors identified in brain, pituitary and spleen have comparable kinetic and pharmacological characteristics, guanine nucleotide sensitivity and adenylate cyclase-stimulating activity. Differences were observed in the molecular mass of the CRF receptor complex between the brain (58,000 Da) and the pituitary and spleen (75,000 Da), which appeared to be due to differential glycosylation of the receptor proteins. The recently cloned CRF receptor in the pituitary and the brain (designated as CRF1) encodes a 415 amino acid protein comprising seven putative membrane-spanning domains and is structurally related to the calcitonin/vasoactive intestinal peptide/growth hormone-releasing hormone subfamily of G-protein-coupled receptors. A second member of the CRF receptor family encoding a 411 amino acid rat brain protein with approximately 70% homology to CRF1 has recently been identified (designated as CRF2); there exists an additional splice variant of the CRF2 receptor with a different N-terminal domain encoding a protein of 431 amino acids. In autoradiographic studies, CRF receptors were localized in highest densities in the anterior and intermediate lobes of the pituitary gland, olfactory bulb, cerebral cortex, amygdala, cerebellum and the macrophage-enriched zones and red pulp regions of the spleen. CRF can modulate the number of CRF receptors in a reciprocal manner. For example, stress and adrenalectomy increase hypothalamic CRF secretion which, in turn, down-regulates CRF receptors in the anterior pituitary. CRF receptors in the brain and pituitary are also altered as a consequence of the development and aging processes. In addition to a physiological role for CRF in integrating the responses of the brain, endocrine and immune systems to physiological, psychological and immunological stimuli, recent clinical data implicate CRF in the etiology and pathophysiology of various endocrine, psychiatric, neurologic and inflammatory illnesses. Hypersecretion of CRF in the brain may contribute to the symptomatology seen in neuropsychiatric disorders, such as depression, anxiety-related disorders and anorexia nervosa. Furthermore, overproduction of CRF at peripheral inflammatory sites, such as synovial joints may contribute to autoimmune diseases such as rheumatoid arthritis. In contrast, deficits in brain CRF are apparent in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, as they relate to dysfunction of CRF neurons in the brain areas affected in the particular disorder. Strategies directed at developing CRF-related agents may hold promise for novel therapies for the treatment of these various disorders.
促肾上腺皮质激素释放因子（CRF）通过在脑和外周的作用，在协调对压力的内分泌、自主神经、行为和免疫反应中起主要作用。在脑、垂体和脾脏中鉴定出的CRF受体具有可比的动力学和药理学特性、鸟嘌呤核苷酸敏感性和腺苷酸环化酶刺激活性。在脑（58,000 Da）与垂体和脾脏（75,000 Da）之间观察到CRF受体复合物分子量的差异，这似乎是由于受体蛋白糖基化的差异所致。最近在垂体和脑中克隆的CRF受体（命名为CRF1）编码一种415个氨基酸的蛋白质，包含七个假定的跨膜结构域，并且在结构上与G蛋白偶联受体的降钙素/血管活性肠肽/生长激素释放激素亚家族相关。最近已鉴定出CRF受体家族的第二个成员，它编码一种与CRF1具有约70%同源性的411个氨基酸的大鼠脑蛋白（命名为CRF2）；CRF2受体还存在另一种剪接变体，其具有不同的N末端结构域，编码一种431个氨基酸的蛋白质。在放射自显影研究中，CRF受体在垂体前叶和中叶、嗅球、大脑皮层、杏仁核、小脑以及脾脏富含巨噬细胞的区域和红髓区域中密度最高。CRF可以以相互的方式调节CRF受体的数量。例如，应激和肾上腺切除术会增加下丘脑CRF的分泌，这反过来又会下调垂体前叶中的CRF受体。脑和垂体中的CRF受体也会因发育和衰老过程而发生改变。除了CRF在整合脑、内分泌和免疫系统对生理、心理和免疫刺激的反应中的生理作用外，最近的临床数据表明CRF与各种内分泌、精神、神经和炎症性疾病的病因和病理生理学有关。脑中CRF的过度分泌可能导致神经精神疾病中出现的症状，如抑郁症、焦虑相关疾病和神经性厌食症。此外，在周围炎症部位如滑膜关节中CRF的过度产生可能导致自身免疫性疾病如类风湿性关节炎。相反，在神经退行性疾病如阿尔茨海默病、帕金森病和亨廷顿病中，脑CRF的缺乏很明显，因为它们与特定疾病中受影响脑区的CRF神经元功能障碍有关。针对开发与CRF相关药物的策略可能为治疗这些各种疾病的新疗法带来希望。
