Axonal protein synthesis and the regulation of primary afferent function.
Bottom Line: Local protein synthesis has been demonstrated in the peripheral processes of sensory primary afferents and is thought to contribute to the maintenance of the neuron, to neuronal plasticity following injury and also to regeneration of the axon after damage to the nerve.The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, integrates a variety of cues that regulate cellular homeostasis and is thought to play a key role in coordinating the neuronal response to environmental challenges.Given the role of mTORC1 in cellular homeostasis, it seems that systemic changes in the physiological state of the body such as occur during illness are likely to modulate the sensitivity of peripheral sensory afferents through mTORC1 signaling pathways.
Affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; School of Medicine, Pharmacy and Health, Durham University, Stockton-on-Tees TS17 6BH, United Kingdom.Show MeSH
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Mentions: Recently, it was demonstrated that a subset of sensory axons in adult rat and mouse cutaneous tissues contained an activated form the mammalian target of rapamycin, a serine/threonine protein kinase phosphorylated at serine 2448 (phospho-mTOR, P-mTOR) (Jimenez-Diaz et al., 2008; Geranton et al., 2009; Melemedjian et al., 2011; Obara et al., 2011a, 2011b; Verma et al., 2005). Using markers that distinguish C- from A-fibers, we were able to show immunohistochemically that P-mTOR+ fibers were almost exclusively A-fibers characteristically terminating within the dermis in contrast to C-fibers which often enter the overlying epidermis [Fig. 1(A–C, D–F)] (Jimenez-Diaz et al., 2008). mTOR is a master regulator of protein synthesis integrating a variety of environmental cues to regulate cellular homeostasis (Laplante and Sabatini, 2012). mTOR forms at least two multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (Zoncu et al., 2011; Magnuson et al., 2012). mTORC1 is fairly well understood and recognized as an environmental sensor with acute sensitivity to rapamycin but far less is known about TORC2 (Zoncu et al., 2011). In a phosphorylated, active form mTORC1 can activate downstream pathways and has been shown to promote protein synthesis in cell bodies, axons, and dendrites (Costa-Mattioli et al., 2009). Ribosomal protein S6K (S6 kinase) and 4EBP (eIF4E; eukaryotic initiation factor 4E-binding protein) are well-characterized substrates for mTORC1. S6K activation absolutely requires TORC1-mediated phosphorylation and phosphorylates its own set of targets, many of which promote protein production (Magnuson et al., 2012). In a parallel pathway, TORC1-mediated phosphorylation of 4EBP1 initiates cap-dependent translation by eIF4E. Thus, TORC1 signals along parallel pathways to co-ordinately promote protein synthesis (Ekim et al., 2011; Magnuson et al., 2012).
Affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; School of Medicine, Pharmacy and Health, Durham University, Stockton-on-Tees TS17 6BH, United Kingdom.