Zagon Ian S, Verderame Michael F, McLaughlin Patricia J
Department of Neuroscience and Anatomy, H-109, The Milton S. Hershey Medical Center, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Brain Res Brain Res Rev. 2002 Feb;38(3):351-76. doi: 10.1016/s0165-0173(01)00160-6.
Opioid peptides act as growth factors in neural and non-neural cells and tissues, in addition to serving for neurotransmission/neuromodulation in the nervous system. The native opioid growth factor (OGF), [Met(5)]-enkephalin, is a tonic inhibitory peptide that plays a role in cell proliferation and tissue organization during development, cancer, cellular renewal, wound healing, and angiogenesis. OGF action is mediated by a receptor mechanism. Assays with radiolabeled OGF have detected specific and saturable binding, with a one-site model of kinetics. Subcellular fractionation studies show that the receptor for OGF (OGFr) is an integral membrane protein associated with the nucleus. Using antibodies generated to a binding fragment of OGFr, this receptor has been cloned and sequenced in human, rat, and mouse. OGFr is distinguished by containing a series of imperfect repeats. The molecular and protein structure of OGFr have no resemblance to that of classical opioid receptors, and have no significant homologies to known domains or functional motifs with the exception of a bipartite nuclear localization signal. Immunoelectron microscopy and immunocytochemistry investigations, including co-localization studies, have detected OGFr on the outer nuclear envelope where it interfaces with OGF. The peptide-receptor complex associates with karyopherin, translocates through the nuclear pore, and can be observed in the inner nuclear matrix and at the periphery of heterochromatin of the nucleus. Signal transduction for modulation of DNA activity is dependent on the presence of an appropriate confirmation of peptide and receptor. This report reviews the history of OGF-OGFr, examines emerging insights into the mechanisms of action of opioid peptide-receptor interfacing, and discusses the clinical significance of these observations.
阿片肽除了在神经系统中发挥神经传递/神经调节作用外，还在神经和非神经细胞及组织中充当生长因子。天然阿片生长因子（OGF），即[Met(5)]-脑啡肽，是一种张力抑制肽，在发育、癌症、细胞更新、伤口愈合和血管生成过程中的细胞增殖和组织构建中发挥作用。OGF的作用由一种受体机制介导。用放射性标记的OGF进行的检测已检测到特异性和可饱和结合，其动力学符合单点模型。亚细胞分级分离研究表明，OGF受体（OGFr）是一种与细胞核相关的整合膜蛋白。利用针对OGFr结合片段产生的抗体，已在人、大鼠和小鼠中克隆并测序了该受体。OGFr的特点是含有一系列不完全重复序列。OGFr的分子和蛋白质结构与经典阿片受体不同，除了一个双分核定位信号外，与已知结构域或功能基序没有明显的同源性。免疫电子显微镜和免疫细胞化学研究，包括共定位研究，已在与OGF相互作用的外核膜上检测到OGFr。肽-受体复合物与核转运蛋白结合，通过核孔转运，并可在内核基质和细胞核异染色质周边观察到。DNA活性调节的信号转导取决于肽和受体的适当构象的存在。本报告回顾了OGF-OGFr的历史，审视了对阿片肽-受体相互作用作用机制的新见解，并讨论了这些观察结果的临床意义。
