Abstract
Neurotrophins are secreted proteins that regulate neuronal development and survival, as well as maintenance and plasticity of the adult nervous system. The biological activity of neurotrophins stems from their binding to two membrane receptor types, the tropomyosin receptor kinase and the p75 neurotrophin receptors (NRs). The intracellular signalling cascades thereby activated have been extensively investigated. Nevertheless, a comprehensive description of the ligand-induced nanoscale details of NRs dynamics and interactions spanning from the initial lateral movements triggered at the plasma membrane to the internalization and transport processes is still missing. Recent advances in high spatio-temporal resolution imaging techniques have yielded new insight on the dynamics of NRs upon ligand binding. Here we discuss requirements, potential and practical implementation of these novel approaches for the study of neurotrophin trafficking and signalling, in the framework of current knowledge available also for other ligand-receptor systems. We shall especially highlight the correlation between the receptor dynamics activated by different neurotrophins and the respective signalling outcome, as recently revealed by single-molecule tracking of NRs in living neuronal cells.
Highlights
Neurotrophins (NTs) are a family of neuronal growth factors that crucially regulate cell survival, differentiation, neurite outgrowth, as well as cell maintenance, neurite regeneration and synaptic plasticity in both the central and peripheral nervous system (CNS and PNS, respectively) [1,2]
The main reasons for this are at least three: (i) By GFP fusion to the TrkA receptor both the intracellular and membrane pools of protein are labeled and discriminating the two of them requires the use of high resolution imaging techniques such as TIRF microscopy [65]; (ii) the GFP fluorophore displays poor photophysical properties at the single-molecule level and tracking of GFP-tagged single receptors is not feasible for long-enough time to retrieve reliable information about the oligomerization state [87]; and (iii) the alternative use of fluorophore-conjugated nerve growth factor (NGF) only allows the study of TrkA receptor in its activated form, likely in the presence of p75 neurotrophin receptor (p75NTR) co-receptor, so that the net effect of ligand binding on the membrane mobility of a single receptor is not possible
The details of neurotrophin receptors (NRs) dynamics at the plasma membrane started to be elucidated both in resting conditions and following ligand stimulation
Summary
Neurotrophins (NTs) are a family of neuronal growth factors that crucially regulate cell survival, differentiation, neurite outgrowth, as well as cell maintenance, neurite regeneration and synaptic plasticity in both the central and peripheral nervous system (CNS and PNS, respectively) [1,2]. The nanoscale details of molecular specificity achieved by NRs upon recognition of different available NTs and/or their respective unprocessed forms are poorly understood This information would likely provide the mechanistic link between the initial lateral movements triggered at the plasma membrane upon ligand binding, their internalization and transport processes, and their respective biological outcome. More recently the conjugation of NTs or NRs to bright and photostable fluorophores together with the use of high-performance wide-field and video-rate microscopy have opened the way to studies of imaging and tracking of few or SM of the species of interest in living cells Such approaches make it possible to probe membrane or intracellular diffusion, oligomerization state and axonal transport of NRs with detail down to the nanoscale. Microtubules control GlyR lateral diffusion in the extra-synaptic membrane, actin at the synapses
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