Abstract
The neurotrophin nerve growth factor (NGF) binds to two receptor types: the tyrosine kinase receptor TrkA and the common neurotrophin receptor p75NTR. 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 p75NTR, consistent with the direct interactions of the antagonist with NGF. In addition, we demonstrate that the ability of PD90780 to inhibit NGF-p75NTR interactions is lower when receptors are coexpressed, compared with when p75NTR is the only neurotrophin receptor expressed. These results suggest that the interaction between NGF and the p75NTR 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 p75NTR when expressed in the absence of TrkA, although having less effect on the pro-survival effects of p75NTR mediated by enhanced TrkA activation.
Footnotes
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This research was supported by the Canadian Institutes for Health Research (MOP-42403 to G.M.R. and MOP-7757 to R.J.R.) and by the Neuromuscular Research Partnership Program (an alliance of the Amyotrophic Lateral Sclerosis Society of Canada, the Muscular Dystrophy Association, and the Canadian Institutes for Health Research; JNM-48405 to G.M.R.). G.M.R. is a Queen's National Scholar.
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DOI: 10.1124/jpet.104.066225.
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ABBREVIATIONS: NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; HKR, HEPES-Krebs-Ringer; BS3, bis-(sulfosuccinimidyl) suberate; TBS, Tris-buffered saline; PAGE, polyacrylamide gel electrophoresis; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; SNHS, sulfo-N-hydroxy-sulfosuccinimide; NT-3, neurotrophin-3; CI, confidence interval; PD90780, 7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid; Ro 08-2870, 2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo[g]pteridine-8-carboxaldehyde; ALE-0540, N-{5-nitro-1H-benz[de]isoquinoline-1,3(2H)-dione}-2-aminoethanol.
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↵1 Current Address: Department of Medicinal Chemistry, AstraZeneca R&D Lund, S-22187 Lund, Sweden.
- Received January 27, 2004.
- Accepted March 26, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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