DISRUPTION OF NGF BINDING TO THE LOW-AFFINITY NEUROTROPHIN RECEPTOR P75(LNTR) REDUCES NGF BINDING TO TRKA ON PC12 CELLS

The role of the low affinity neurotrophin receptor, p75(LNTR), in NGF-mediated signal transduction has been examined. Our results show that treatment of PC12 cells with MC192, a monoclonal antibody directed against p75(LNTR), results in reduced NGF binding to TrkA and attenuated TrkA activation. Use of mutant NGF that binds TrkA but not p75(LNTR) shows that the MC192 effect requires that NGF bind the p75(LNTR) receptor. To explore the possibility that MC192 disrupts some normal functional role of p75(LNTR), BDNF was used to block binding of NGF to p75(LNTR) on PC12 cells. By preventing NGF binding to p75(LNTR), NGF binding to TrkA and NGF-mediated signal transduction were reduced. We propose that p75(LNTR) normally acts to increase binding of NGF to TrkA, possibly by increasing the local NGF concentration in the microenvironment surrounding the cell surface TrkA receptor.