RECIPROCAL MODULATION OF TRKA AND P75(NTR) AFFINITY STATES IS MEDIATED BY DIRECT RECEPTOR INTERACTIONS

Equilibrium binding of I-125-nerve growth factor (I-125-NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotro phin receptor (p75(NTR)), cells coexpressing both receptors where p75( NTR) is occupied, and cells expressing only p75(NTR), revealed recipro cal modulation of receptor affinity states, Analysis of receptor affin ity states in PC12 cells, PC12 cells in the presence of brain-derived neurotrophic factor (BDNF), and PC12(nnr5) cells suggested that ligand ed 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 T rkA/p75(NTR) complexes in the absence of NGF. Chemical crosslinking st udies revealed high molecular weight receptor complexes that specifica lly bound I-125-NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75(NTR) alters con formation and/or dissociates in the presence of NGF, as indicated by t he ability of low concentrations of NGF to prevent heteroreceptor cros slinking. These data suggest a new model of receptor interaction, wher eby structural changes within a heteroreceptor complex are induced by ligand binding.