Activin acts with nerve growth factor to regulate calcitonin gene-related peptide mRNA in sensory neurons

Abstract

Calcitonin Gene-Related Peptide (CGRP) increases in sensory neurons after inflammation and plays an important role in abnormal pain responses, but how this neuropeptide is regulated is not well understood. Both activin A and Nerve Growth Factor (NGF) increase in skin after inflammation and induce CGRP in neurons in vivo and in vitro. This study was designed to understand how neurons integrate these two signals to regulate the neuropeptide important for inflammatory pain. In adult dorsal root ganglion neurons, NGF but not activin alone produced a dose-dependent increase in CGRP mRNA. When added together with NGF, activin synergistically increased CGRP mRNA, indicating that sensory neurons combine these signals. Studies were then designed to learn if that combination occurred at a common receptor or shared intracellular signals. Studies with Activin IB receptor or trkA inhibitors suggested that each ligand required its cognate receptor to stimulate the neuropeptide. Further, activin did not augment NGF-initiated intracellular MAPK signals but instead stimulated Smad phosphorylation, suggesting these ligands initiated parallel signals in the cytoplasm. Activin synergy required several NGF intracellular signals to be present. Because activin did not further stimulate, but did require NGF intracellular signals, it appears that activin and NGF converge not in receptor or cytoplasmic signals, but in transcriptional mechanisms to regulate CGRP in sensory neurons after inflammation. Keywords inflammation; neuropeptides; ERK; SmadHyperalgesia is a key sign of inflammation and is initiated by signals from inflamed tissues that act on sensory neurons to modify molecules involved in pain behaviors. The central mechanism of hyperalgesia involves the hyperexcitablility of dorsal horn neurons, which can be attenuated by blocking glutamate receptors Inturrisi, 2001, Yashpal et al., 2001), neurokinin receptors (Malmberg and Yaksh, 1992, Thompson et al., 1994) and CGRP receptors (Sun et al., 2004) in the spinal cord. Indeed, alpha-CGRP null mice do not develop hyperalgesia responses to inflammatory insults (Salmon et al., 2001, Zhang et al., 2001). The neuropeptide calcitonin gene related peptide (CGRP) is increased in sensory neurons after peripheral inflammation (Donaldson et al., 1992, Smith et al., 1992, Donnerer et al., 1993, Nahin and Byers, 1994, Seybold et al., 1995, Neumann et al., 1996, Malcangio et al., 1997, Mulder et al., 1997b, Durham and Russo, 1999, Calza et al., 2000, Bulling et al., 2001 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Salmon et al., 2001, Zha...

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

“…B-RAF-mediated axon growth indirectly rescues calcitonin gene-related peptide (CGRP) expression in TrkA / :Bax / neurons CGRP expression in the peptidergic subset of nociceptive DRG neurons is induced by skin-derived factors and therefore indicates that sensory axon peripheral innervation into the skin is complete (Hall et al, 1997(Hall et al, , 2001Patel et al, 2000;Xu and Hall, 2007). In TrkA / :Bax / mice, DRG neurons and their centrally projecting axons are devoid of CGRP because of the lack of cutaneous innervation as previously described (Patel et al, 2000), whereas CGRP expression in the spinal motor neurons remains unaffected (Fig.…”

Transforming Growth Factor-β in Normal Nociceptive Processing and Pathological Pain Models

“…This effect involves the canonical Smad pathway [45,56]. In postnatal DRG cultures, recombinant activin increases CGRP expression [56][57][58][59], while TGF-β1 and TGF-β2 increase the levels SP [59]. The effect of these cytokines on neuropeptide expression is synergistic with NGF, which led the authors to hypothesize that a cooperative interaction between Smads and NGF-dependent transcription factors further increases neuropeptide transcription [59].…”

“…In postnatal DRG cultures, recombinant activin increases CGRP expression [56][57][58][59], while TGF-β1 and TGF-β2 increase the levels SP [59]. The effect of these cytokines on neuropeptide expression is synergistic with NGF, which led the authors to hypothesize that a cooperative interaction between Smads and NGF-dependent transcription factors further increases neuropeptide transcription [59]. Overall, these data support a role for TGF-β family members as target-derived differentiation factors that contribute to the specification of the functional identity of neuropeptidecontaining neurons during development.…”

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