Activation of Trk neurotrophin receptors in the absence of neurotrophins

被引:396
作者
Lee, FS
Chao, MV [1 ]
机构
[1] NYU, Sch Med, Mol Neurobiol Program, Skirball Inst Biomol Med,Dept Cell Biol & Physiol, New York, NY 10016 USA
[2] NYU, Sch Med, Mol Neurobiol Program, Skirball Inst Biomol Med,Dept Neurosci, New York, NY 10016 USA
关键词
D O I
10.1073/pnas.061020198
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Neurotrophins regulate neuronal cell survival and synaptic plasticity through activation of Trk receptor tyrosine kinases. Binding of neurotrophins to Trk receptors results in receptor autophosphorylation and downstream phosphorylation cascades. Here, we describe an approach to use small molecule agonists to transactivate Trk neurotrophin receptors, Activation of TrkA receptors in PC12 cells and TrkB in hippocampal neurons was observed after treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors. These effehs were reproduced by using the adenosine agonist CGS 21680 and were counteracted with the antagonist ZM 241385, indicating that this transactivation event by adenosine involves adenosine ZA receptors; The increase in Trk activity could be inhibited by the use of the Src family-specific inhibitor, PP1, or K252a, an inhibitor of Trk receptors. In contrast to other G protein-coupled receptor transactivation events, adenosine used Trk receptor signaling with a longer time course. Moreover, adenosine activated phosphatidylinositol 3-kinase/Akt through a Trk-dependent mechanism that resulted in increased cell survival after nerve growth factor or brain-derived neurotrophic factor withdrawal. Therefore, adenosine acting through the AZA receptors exerts a trophic effect through the engagement of Trk receptors, These results provide an explanation for neuroprotective actions of adenosine through a unique signaling mechanism and raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases.
引用
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页码:3555 / 3560
页数:6
相关论文
共 52 条
[1]  
Aibel L, 1998, J NEUROSCI RES, V54, P424, DOI 10.1002/(SICI)1097-4547(19981101)54:3<424::AID-JNR13>3.0.CO
[2]  
2-6
[3]  
BERG MM, 1992, J BIOL CHEM, V267, P13
[4]   Neurotrophins and activity-dependent development of the neocortex [J].
Bonhoeffer, T .
CURRENT OPINION IN NEUROBIOLOGY, 1996, 6 (01) :119-126
[5]  
CASTELLINO AM, 1997, CYTOKINE GROWTH F R, V7, P297
[6]   P75 AND TRK - A 2-RECEPTOR SYSTEM [J].
CHAO, MV ;
HEMPSTEAD, BL .
TRENDS IN NEUROSCIENCES, 1995, 18 (07) :321-326
[7]   A BRANCHED SIGNALING PATHWAY FOR NERVE GROWTH-FACTOR IS REVEALED BY SRC-MEDIATED, RAS-MEDIATED, AND RAF-MEDIATED GENE INDUCTIONS [J].
DARCANGELO, G ;
HALEGOUA, S .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (06) :3146-3155
[8]   Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors [J].
Daub, H ;
Weiss, FU ;
Wallasch, C ;
Ullrich, A .
NATURE, 1996, 379 (6565) :557-560
[9]   Signal characteristics of G protein-transactivated EGF receptor [J].
Daub, H ;
Wallasch, C ;
Lankenau, A ;
Herrlich, A ;
Ullrich, A .
EMBO JOURNAL, 1997, 16 (23) :7032-7044
[10]   Tissue distribution of adenosine receptor mRNAs in the rat [J].
Dixon, AK ;
Gubitz, AK ;
Sirinathsinghji, DJS ;
Richardson, PJ ;
Freeman, TC .
BRITISH JOURNAL OF PHARMACOLOGY, 1996, 118 (06) :1461-1468