Reciprocal modulation of TrkA and p75NTR affinity states is mediated by direct receptor interactions.
Equilibrium binding of 125I-nerve growth factor (125I-NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotrophin receptor (p75NTR), cells coexpressing both receptors where p75NTR is occupied, and cells expressing only p75NTR, 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 PC12nnr5 cells suggested that liganded and unliganded p75NTR induce a higher affinity state within TrkA, while TrkA induces a lower affinity state within p75NTR. These data are consistent with receptor allosterism, and prompted a search for TrkA/p75NTR complexes in the absence of NGF. Chemical crosslinking studies revealed high molecular weight receptor complexes that specifically bound 125I-NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75NTR 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.
Ross
G M
GM
Department of Medicine, Kingston General Hospital, Ontario, Canada.
Shamovsky
I L
IL
Lawrance
G
G
Solc
M
M
Dostaler
S M
SM
Weaver
D F
DF
Riopelle
R J
RJ
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003432:Cross-Linking Reagents; D008024:Ligands; D008959:Models, Neurological; D008970:Molecular Weight; D009414:Nerve Growth Factors / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D003432:Cross-Linking Reagents; D008024:Ligands; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA