Differential activity of the nerve growth factor (NGF) antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid] suggests altered NGF-p75NTR interactions in the presence of TrkA
Differential activity of the nerve growth factor (NGF) antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid] suggests altered NGF-p75NTR interactions in the presence of TrkA
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DOI：
10.1124/jpet.104.066225
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发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Ross, GM
中科院分区：
文献类型：
--
作者：
Colquhoun, A;Lawrance, GM;Ross, GM
神经营养因子神经生长因子（NGF）结合两种受体类型：酪氨酸激酶受体TrkA和共同神经营养因子受体p75（NTR）。尽管NGF的许多生物学效应（如神经元生长和存活）与TrkA活化相关，但当受体共表达时，p75 NTR也通过增强TrkA的作用而有助于这些活性。NGF拮抗剂PD 90780 [7-（苯甲酰氨基）-4，9-二氢-4-甲基-9-氧代-吡唑并[5，1-B]喹唑啉-2-羧酸]与NGF相互作用，阻止其与p75 NTR结合。在本研究中，进一步探索了该化合物的作用，发现PD 90780不能抑制脑源性神经营养因子或神经营养素-3与p75（NTR）的结合，这与拮抗剂与NGF的直接相互作用一致。此外，我们证明了PD 90780抑制NGF-p75（NTR）相互作用的能力是较低的受体共表达时，与p75（NTR）是唯一的神经营养因子受体表达。这些结果表明，当TrkA共表达时，NGF和p75（NTR）受体之间的相互作用被改变。这种改变可用于开发拮抗剂，当在不存在TrkA的情况下表达时，所述拮抗剂将选择性地抑制p75（NTR）的促凋亡作用，尽管对由增强的TrkA活化介导的p75（NTR）的促存活作用具有较小的影响。
The neurotrophin nerve growth factor (NGF) binds to two receptor types: the tyrosine kinase receptor TrkA and the common neurotrophin receptor p75(NTR). Although many of the biological effects of NGF ( such as neuronal growth and survival) are associated with TrkA activation, p75NTR also contributes to these activities by enhancing the action of TrkA when receptors are coexpressed. The NGF antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl- 9-oxo-pyrazolo[5,1-b] quinazoline-2-carboxlic acid] interacts with NGF, preventing its binding to p75NTR. In this study, the actions of this compound are further explored, and it is found that PD90780 is not able to inhibit the binding of either brain-derived neurotrophic factor or neurotrophin-3 to p75(NTR), consistent with the direct interactions of the antagonist with NGF. In addition, we demonstrate that the ability of PD90780 to inhibit NGF-p75(NTR) interactions is lower when receptors are coexpressed, compared with when p75(NTR) is the only neurotrophin receptor expressed. These results suggest that the interaction between NGF and the p75(NTR) receptor is altered when TrkA is coexpressed. This alteration can be exploited in the development of antagonists that will selectively inhibit the pro-apoptotic actions of p75(NTR) when expressed in the absence of TrkA, although having less effect on the pro-survival effects of p75(NTR) mediated by enhanced TrkA activation.