Coupling of death receptor p75NTR to the RhoA and NF-kB pathways differentially regulates internalization in hippocampal and cerebellar neurons

Receptor internalization regulates the duration and qualitative output of intracellular signaling. Although generic mechanisms of receptor internalization are well characterized, how these are deployed and regulated in different cell types remains much less understood. Here we show that the p75 neurotrophin receptor (p75NTR), a key regulator of neuron survival and function, internalizes in hippocampal (HCNs)and cerebellar granule (CGNs)neurons with very different kinetics, regulated by distinct mechanisms. Compared to HCNs, p75NTR internalizes at a much slower rate and shows stronger interaction with caveolin in CGNs. In both cell types, p75NTR internalization was enhanced by nerve growth factor (NGF)but reduced by inhibitors of the RhoA and PKC pathways. In line with this, internalization of a p75NTR mutant specifically impaired in RhoA signaling was significantly reduced and insensitive to NGF in both neuron types. Accordingly, this mutant showed a much stronger interaction with caveolin than wild type p75NTR. On the other hand, internalization of a mutant specifically impaired in coupling to the NF-kB signaling pathway was greatly accelerated in CGNs but unaffected in HCNs. These results reveal the crucial role of intracellular signaling in p75NTR internalization and demonstrate that the receptor is differentially wired to the endocytosis machinery in different neuron types, leading to distinct internalization behaviors.