The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein, and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discuss the physiopathological implications of these regulatory gliopeptides.

中文翻译：

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内zepines及其受体：结构，功能和病理生理意义。

脑中苯二氮卓类药物（BZs）的特异性结合位点的存在促使人们搜寻以通用术语“内啡肽”命名的内源性BZ受体配体。这导致鉴定出能够置换[3H]地西am与脑膜结合的86个氨基酸的多肽，因此被称为地西epa结合抑制剂（DBI）。随后发现，DBI的序列与称为酰基辅酶A结合蛋白（ACBP）的脂质载体蛋白的序列相同。DBI / ACBP的主要结构已保存完好，表明内啡肽发挥重要作用。DBI / ACBP基因由中枢神经系统中的星形胶质细胞和外周器官中的各种细胞类型表达。DBI / ACBP的内切酶裂解产生了几种生物活性肽，包括充当外周BZ受体/转运蛋白的选择性配体的triakontatetraneuropeptide和激活G蛋白偶联受体并起GABAAR变构调节剂作用的十八烯肽。尽管DBI / ACBP没有信号肽，但内啡肽由星形胶质细胞以受控方式释放。与BZ结合位点的多样性和广泛分布一致，内啡肽似乎发挥了许多生物学功能和药理作用。因此，脑室内给予DBI或衍生肽会引起前冲和焦虑样行为，并减少食物摄入量。相反，DBI / ACBP mRNA的表达受压力和代谢信号的调节。体外，内啡肽刺激星形胶质细胞增殖并保护神经元和星形胶质细胞免受凋亡性细胞死亡。内氮卓类还调节神经固醇的生物合成和神经肽表达，并促进神经发生。内啡肽在周围器官中激活类固醇激素的产生，刺激酰基链神经酰胺的合成并触发促炎性细胞因子的分泌。在成瘾/戒断动物模型，神经退行性疾病患者和各种类型的肿瘤中，DBI / ACBP基因的表达得到增强。我们在这里回顾了有关内啡肽的各种作用的当前知识，并讨论了这些调节性gliopepteptides的生理病理意义。内氮卓类还调节神经固醇的生物合成和神经肽表达，并促进神经发生。内啡肽在周围器官中激活类固醇激素的产生，刺激酰基链神经酰胺的合成并触发促炎性细胞因子的分泌。在成瘾/戒断动物模型，神经退行性疾病患者和各种类型的肿瘤中，DBI / ACBP基因的表达得到增强。我们在这里回顾了有关内啡肽的各种作用的当前知识，并讨论了这些调节性gliopepteptides的生理病理意义。内啡肽还调节神经固醇的生物合成和神经肽表达，并促进神经发生。内啡肽在周围器官中激活类固醇激素的产生，刺激酰基链神经酰胺的合成并触发促炎性细胞因子的分泌。在成瘾/戒断动物模型，神经退行性疾病患者和各种类型的肿瘤中，DBI / ACBP基因的表达得到增强。我们在这里回顾了有关内啡肽各种作用的当前知识，并讨论了这些调节性糖肽的生理病理学意义。在成瘾/戒断动物模型，神经退行性疾病患者和各种类型的肿瘤中，DBI / ACBP基因的表达得到增强。我们在这里回顾了有关内啡肽各种作用的当前知识，并讨论了这些调节性糖肽的生理病理学意义。在成瘾/戒断动物模型，神经退行性疾病患者和各种类型的肿瘤中，DBI / ACBP基因的表达得到增强。我们在这里回顾了有关内啡肽的各种作用的当前知识，并讨论了这些调节性gliopepteptides的生理病理意义。