Translating nociceptor sensitivity: the role of axonal protein synthesis in nociceptor physiology

Abstract

The increased sensitivity of peripheral pain-sensing neurons, or nociceptors, is a major cause of the sensation of pain that follows injury. This plasticity is thought to contribute to the maintenance of chronic pain states. Although we have a broad knowledge of the factors that stimulate changes in nociceptor sensitivity, the cellular mechanisms that underlie this plasticity are still poorly understood; however, they are likely to involve changes in gene expression required for the phenotypic and functional changes seen in nociceptive neurons after injury. While the regulation of gene expression at the transcriptional level has been studied extensively, the regulation of protein synthesis, which is also a tightly controlled process, has only recently received more attention. Despite the established role of protein synthesis in the plasticity of neuronal cell bodies and dendrites, little attention has been paid to the role of translation control in mature undamaged axons. In this regard, several recent studies have demonstrated that the control of protein synthesis within the axonal compartment is crucial for the normal function and regulation of sensitivity of nociceptors. Pathways and proteins regulating this process, such as the mammalian target of rapamycin signaling cascade and the fragile X mental retardation protein, have recently been identified. We review here recent evidence for the regulation of protein synthesis within a nociceptor's axonal compartment and its contribution to this neuron's plasticity. We believe that an increased understanding of this process will lead to the identification of novel targets for the treatment of chronic pain.

Fig. 1

Mechanisms of translation control of gene expression. At least three mechanisms have been identified via which extracellular signals can regulate the rate-limiting step of translation, initiation (Star 1 to 3). (Star 1) The kinase mTOR can be activated downstream of PI3Kinase/AKT signaling and under certain circumstances by ERK. The primary target for mTOR (when it is associated with raptor, forming the mTORC1 complex) is 4E-BP. When 4E-BP is not phosphorylated, it binds to eIF4E and suppresses translation. When 4E-BP is phosphorylated it dissociates from eIF4E, allowing the binding of eIF4G and the modulation of eIF4E activity by ERK/MNK1 signaling. mTOR also phosphorylates S6 kinase (S6K), leading to phosphorylation of eIF4B and ribosomal S6 protein (rS6). (Star 2) ERK and p38 signal via MNK1 to increase eIF4E phosphorylation. This phosphorylation of eIF4E is linked to an increased affinity for eIF4G and the formation of this complex is involved in the recruitment of the 40S ribosomal subunit. (Star 3) The initiation factor eIF2α, when unphosphorylated, is also involved in the recruitment of the 40S ribosome subunit. eIF2α is phosphorylated by GCN2 in conditions of cellular stress, and genetic modulation of eIF2α phosphorylation has shown that eIF2α plays an important role in synaptic plasticity. (Star 4) A subset of mRNAs contain a 5′ terminal oligopyrimidine tract (TOP) and largely encode ribosomal proteins and elongation initiation factors. Increased mTOR activity is positively linked to the translation of these mRNAs as well as rS6 phosphorylation; however, genetic studies clearly show that rS6 is dispensable for this effect. (Star 5) Translation is also regulated by mRNA localization, miRNAs and the miRNA pathway. Key RNA binding proteins involved in RNA localization in neurons are staufen (which binds to hairpins) and FMRP (which binds to G-quartets, among other structures and sequences). FMRP has also been shown to bind to miRNAs and proteins involved in the miRNA pathway such as dicer and argonaute (AGO1).

Fig. 2

Similarities between translation control in CNS dendrites and PNS axons. Advances in our understanding of how translation can be controlled at distal sites in neurons has shown a number of parallels between translation control in CNS dendrites (which is linked to synaptic plasticity) and in PNS axons (which is linked to regeneration, repair and nociceptive plasticity). Both of these structures contain initiation factors (4E-BP and eIF4E), kinases that signal to initiation factors (mTOR and ERK), RNA binding proteins (FMRP and staufen), a diverse subset of mRNAs, miRNAs and miRNA pathway components (dicer and argonaute) and Golgi outposts for the proper processing of transmembrane and other proteins (TGN38 and GM130). Many of these components and related mechanisms have been experimentally linked to synaptic plasticity in CNS dendrites (red stars). Many of them have also been shown to be involved in PNS axon regeneration, repair and/or nociceptive plasticity (red stars).

Fig. 3

Identified and potential key players involved in the regulation of translation in the axonal compartment and nociceptor plasticity. The available evidence suggests that mTOR activity is critical for maintaining the sensitivity of a subset of nociceptive neurons and that mTOR is also an important mediator of chemically-mediated nociceptor plasticity. Rapamycin, a specific inhibitor of mTOR activity, is a powerful tool for regulating protein synthesis of TOP mRNAs. Furthermore, findings from studies in FMRP-KO mice suggest that FMRP is crucial for mediating activity-dependent synthesis of new proteins that promote the hypersensitivity of nociceptors in response to mGluR1/5 agonists, chemically mediated pain (formalin) and perhaps after nerve injury. Although ERK and/or p38 activity have been positively linked to plasticity after inflammation or nerve injury, its role in regulating translation in the axonal compartment has not yet been explored. However, the availability of a specific MNK1 inhibitor, CGP57380, has been shown to reduce the interaction between eIF4E and eIF4G, making the ERK–p38–MNK1 pathway an attractive target to explore. We propose that gaining a better understanding of how algogens and/or nerve injury modulate the expression of new proteins via these signaling pathways will lead to the discovery of new targets for the control of chronic pain directly at its source either via inhibition of these pathways (e.g. mTOR or ERK) or identification of proteins locally synthesized which may be targets for therapeutic intervention.