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

• Published in: The European journal of neuroscience 1998-03, Vol.10 (3), p.890-898
• Main Authors: Ross, Gregory M, Shamovsky, Igor L, Lawrance, Gail, Solc, Mark, Dostaler, Suzanne M, Weaver, Donald F, Riopelle, Richard J
• Format: Article
• Language: English
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1046/j.1460-9568.1998.00094.x

Equilibrium binding of super(125)I-nerve growth factor ( super(125)I-NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotrophin receptor (p75 super(NTR)), cells coexpressing both receptors where p75 super(NTR) is occupied, and cells expressing only p75 super(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 super(nnr5) cells suggested that liganded and unliganded p75 super(NTR) induce a higher affinity state within TrkA, while TrkA induces a lower affinity state within p75 super(NTR). These data are consistent with receptor allosterism, and prompted a search for TrkA/p75 super(NTR) complexes in the absence of NGF. Chemical crosslinking studies revealed high molecular weight receptor complexes that specifically bound super(125)I-NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75 super(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.