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Reciprocal modulation of TrkA and p75 NTR affinity states is mediated by direct receptor interactions

1998; Wiley; Volume: 10; Issue: 3 Linguagem: Inglês

10.1046/j.1460-9568.1998.00094.x

1460-9568

Gregory M. Ross, Igor L. Shamovsky, Gail Lawrance, Mark Solc, Suzanne M. Dostaler, Donald F. Weaver, Richard J. Riopelle,

Virus-based gene therapy research

Abstract Equilibrium binding of 125 I‐nerve growth factor ( 125 I‐NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotrophin receptor (p75 NTR ), cells coexpressing both receptors where p75 NTR is occupied, and cells expressing only p75 NTR , revealed reciprocal modulation of receptor affinity states. Analysis of receptor affinity states in PC12 cells, PC12 cells in the presence of brain‐derived neurotrophic factor (BDNF), and PC12 nnr5 cells suggested that liganded and unliganded p75 NTR induce a higher affinity state within TrkA, while TrkA induces a lower affinity state within p75 NTR . These data are consistent with receptor allosterism, and prompted a search for TrkA/p75 NTR complexes in the absence of NGF. Chemical crosslinking studies revealed high molecular weight receptor complexes that specifically bound 125 I‐NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75 NTR alters conformation and/or dissociates in the presence of NGF, as indicated by the ability of low concentrations of NGF to prevent heteroreceptor crosslinking. These data suggest a new model of receptor interaction, whereby structural changes within a heteroreceptor complex are induced by ligand binding.