Neurotrophin-TRK complexes can be internalized and enter signalling vesicles, which travel retrogradely over long distances from distal nerve terminals to neuronal cell bodies. Such retrograde signalling by neurotrophin-TRK complexes regulates survival, synaptogenesis and maintenance of proper neural connectivity. The neurotrophin-TRK complex may use three distinct internalization pathways. Although Clathrin-mediated endocytosys appears to be the major internalization route, it is controversial whether it also represents the dominant pathway for retrograde transport and signalling. Pyncher-mediated endocytosis might be more relevant in this regard. Moreover, also caveolin-mediated endocytosis may play a role in NGF-TrkA internalization.
Retrograde transport of TRKs is microtubule-dependent: TRKs remain activated and bound to neurotrophins during retrograde transport. The current view is reflected in the signalling endosome model. It is a specialized vesicle containing ligand (NGF, BDNF) bound to its activated TRK receptor, together with activated downstream signalling proteins, transported by motor proteins (dyneins) from nerve terminals to remote cell bodies, where the receptors trigger signalling cascades.