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RNA control in pain: Blame it on the messenger

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Abstract mRNA function is meticulously controlled. We provide an overview of the integral role that posttranscriptional controls play in the perception of painful stimuli by sensory neurons. These specialized cells, termed nociceptors, precisely regulate mRNA polarity, translation, and stability. A growing body of evidence has revealed that targeted disruption of mRNAs and RNA‐binding proteins robustly diminishes pain‐associated behaviors. We propose that the use of multiple independent regulatory paradigms facilitates robust temporal and spatial precision of protein expression in response to a range of pain‐promoting stimuli. This article is categorized under: RNA in Disease and Development > RNA in Disease Translation > Translation Regulation RNA Turnover and Surveillance > Regulation of RNA Stability
Nociceptor anatomy. Potentially damaging stimuli are sensed by nerve endings in the skin that can detect inflammatory mediators (e.g., NGF, IL6). Nociceptor axons can either be myelinated (i.e., coated with Schwann cells) or unmyelinated. The nociceptor cell body is situated in the trigeminal ganglion or dorsal root ganglion (DRG). Signals received in the skin are relayed by axons back to the dorsal horn of the spinal cord. Information is then forwarded to the central nervous system for further processing via ascending fibers along the spinal cord
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(a) Anatomy of an mRNA. mRNAs are typically capped (black ball). Immediately afterwards is a 5′ untranslated region (UTR) rendered here with a secondary structure that can modulate translation efficiency or mediate bypass of general translation factors. The coding sequences (CDS) contain the primary sequence of the polypeptide that results from translation. This is followed by a 3′ UTR rich in regulatory elements decoded by trans‐acting RNAs (e.g., miRNAs) and RNA‐binding proteins (RBPs). Most mRNAs have a poly(A) tail at the 3′ end. (b) Regulation of cap‐dependent translation initiation. The eIF4F complex containing eIF4A, eIF4E, and eIF4G recruits eIF3 and ribosomes to scan the mRNA for a suitable start codon. This process is controlled by MAPK kinases such as ERK that act via MNK to phosphorylate eIF4E. A second pathway controls eIF4E activity through mammalian target of rapamycin complex 1 (mTORC1) which phosphorylates 4EBPs preventing their association and sequestration of eIF4E. Additionally, the association of eIF4G and the poly(A) binding protein (PAB) stimulates the efficiency of translation initiation. (c) An overview of eIF2α‐dependent translation. Upstream kinases control the activity of eIF2. Phosphorylation of the α‐subunit inhibits the guanine nucleotide exchange factor eIF2B, resulting in bulk translational inhibition
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RNA in Disease and Development > RNA in Disease
RNA Turnover and Surveillance > Regulation of RNA Stability
Translation > Translation Regulation

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