Lai K O, Glass D J, Geis D, Yancopoulos G D, Ip N Y
Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay.
J Neurosci Res. 1996 Dec 1;46(5):618-29. doi: 10.1002/(SICI)1097-4547(19961201)46:5<618::AID-JNR10>3.0.CO;2-T.
Neurotrophins play very important roles in the development and maintenance of the vertebrate nervous system. In mammals, there are four members of the family: NGF, BDNF, NT-3 and NT-4/5. Members of the neurotrophin family activate different receptors that belong to a class of receptor tyrosine kinases known as "Trks." For example, NGF is the specific ligand of TrkA, while BDNF activates TrkB. To elucidate which regions of the two neurotrophins determine the receptor specificities, chimeric neurotrophins were constructed using BDNF as the backbone, with various regions being substituted by the corresponding regions of NGF. The activity of the chimeras on the Trk receptors was assayed in transfected fibroblasts ectopically expressing the Trk receptors. Our findings revealed that, although BDNF is absolutely conserved in mammals, substitution of several small variable regions from NGF into the BDNF backbone did not lead to significant loss in TrkB activity or gain in TrkA activity. Moreover, important determinants of TrkB activation might be located in the carboxy-terminal half of BDNF. On the other hand, critical elements for TrkA activation might be located within the amino-terminal half of the mature NGF molecule.
神经营养因子在脊椎动物神经系统的发育和维持中发挥着非常重要的作用。在哺乳动物中，该家族有四个成员：神经生长因子（NGF）、脑源性神经营养因子（BDNF）、神经营养因子-3（NT-3）和神经营养因子-4/5（NT-4/5）。神经营养因子家族的成员激活不同的受体，这些受体属于一类称为“Trks”的受体酪氨酸激酶。例如，NGF是TrkA的特异性配体，而BDNF激活TrkB。为了阐明这两种神经营养因子的哪些区域决定了受体特异性，构建了以BDNF为骨架的嵌合神经营养因子，其各个区域被NGF的相应区域所取代。在异位表达Trk受体的转染成纤维细胞中测定嵌合体对Trk受体的活性。我们的研究结果表明，尽管BDNF在哺乳动物中是绝对保守的，但将NGF的几个小可变区域替换到BDNF骨架中并不会导致TrkB活性的显著丧失或TrkA活性的增加。此外，TrkB激活的重要决定因素可能位于BDNF的羧基末端一半。另一方面，TrkA激活的关键元件可能位于成熟NGF分子的氨基末端一半内。
