Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation

BACKGROUND: Unilateral injection of Complete Freund's Adjuvant (CFA) into the intra‐plantar surface of the rodent hindpaw elicits chronic inflammation and hyperalgesia in the ipsilateral hindlimb. Mechanisms contributing to this hyperalgesia may act over multiple time courses and can include ch...

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Autores principales: Forster, Lori A., Jansen, Leslie‐Anne R., Rubaharan, Myurajan, Murphy, Anne Z., Baro, Deborah J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496191/
https://www.ncbi.nlm.nih.gov/pubmed/32446289
http://dx.doi.org/10.1002/ejp.1606
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author Forster, Lori A.
Jansen, Leslie‐Anne R.
Rubaharan, Myurajan
Murphy, Anne Z.
Baro, Deborah J.
author_facet Forster, Lori A.
Jansen, Leslie‐Anne R.
Rubaharan, Myurajan
Murphy, Anne Z.
Baro, Deborah J.
author_sort Forster, Lori A.
collection PubMed
description BACKGROUND: Unilateral injection of Complete Freund's Adjuvant (CFA) into the intra‐plantar surface of the rodent hindpaw elicits chronic inflammation and hyperalgesia in the ipsilateral hindlimb. Mechanisms contributing to this hyperalgesia may act over multiple time courses and can include changes in ion channel expression and post‐translational SUMOylation. Hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) channels mediate the hyperpolarization‐activated current, I(h). An HCN2‐mediated increase in C‐nociceptor I(h) contributes to mechanical hyperalgesia in the CFA model of inflammatory pain. Changes in HCN2 post‐translational SUMOylation and protein expression have not been systematically documented for a given dorsal root ganglia (DRG) throughout the time course of inflammation. METHODS: This study examined HCN2 protein expression and post‐translational SUMOylation in a rat model of CFA‐induced hindpaw inflammation. L5 DRG cryosections were used in immunohistochemistry experiments and proximity ligation assays to investigate HCN2 expression and SUMOylation, respectively, on days 1 and 3 post‐CFA. RESULTS: Unilateral CFA injection elicited a significant bilateral increase in HCN2 staining intensity in small diameter DRG neurons on day 1 post‐CFA, and a significant bilateral increase in the number of small neurons expressing HCN2 but not staining intensity on day 3 post‐CFA. HCN2 channels were hyper‐SUMOylated in small diameter neurons of ipsilateral relative to contralateral DRG on days 1 and 3 post‐CFA. CONCLUSIONS: Unilateral CFA injection elicits unilateral mechanical hyperalgesia, a bilateral increase in HCN2 expression and a unilateral increase in post‐translational SUMOylation. This suggests that enhanced HCN2 expression in L5 DRG is not sufficient for mechanical hyperalgesia in the early stages of inflammation and that hyper‐SUMOylation of HCN2 channels may also be necessary. SIGNIFICANCE: Nociceptor HCN2 channels mediate an increase in I(h) that is necessary for mechanical hyperalgesia in a CFA model of chronic pain, but the mechanisms producing the increase in nociceptor I(h) have not been resolved. The data presented here suggest that the increase in I(h) during the early stages of inflammation may be mediated by an increase in HCN2 protein expression and post‐translational SUMOylation.
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spelling pubmed-74961912020-09-25 Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation Forster, Lori A. Jansen, Leslie‐Anne R. Rubaharan, Myurajan Murphy, Anne Z. Baro, Deborah J. Eur J Pain Original Articles BACKGROUND: Unilateral injection of Complete Freund's Adjuvant (CFA) into the intra‐plantar surface of the rodent hindpaw elicits chronic inflammation and hyperalgesia in the ipsilateral hindlimb. Mechanisms contributing to this hyperalgesia may act over multiple time courses and can include changes in ion channel expression and post‐translational SUMOylation. Hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) channels mediate the hyperpolarization‐activated current, I(h). An HCN2‐mediated increase in C‐nociceptor I(h) contributes to mechanical hyperalgesia in the CFA model of inflammatory pain. Changes in HCN2 post‐translational SUMOylation and protein expression have not been systematically documented for a given dorsal root ganglia (DRG) throughout the time course of inflammation. METHODS: This study examined HCN2 protein expression and post‐translational SUMOylation in a rat model of CFA‐induced hindpaw inflammation. L5 DRG cryosections were used in immunohistochemistry experiments and proximity ligation assays to investigate HCN2 expression and SUMOylation, respectively, on days 1 and 3 post‐CFA. RESULTS: Unilateral CFA injection elicited a significant bilateral increase in HCN2 staining intensity in small diameter DRG neurons on day 1 post‐CFA, and a significant bilateral increase in the number of small neurons expressing HCN2 but not staining intensity on day 3 post‐CFA. HCN2 channels were hyper‐SUMOylated in small diameter neurons of ipsilateral relative to contralateral DRG on days 1 and 3 post‐CFA. CONCLUSIONS: Unilateral CFA injection elicits unilateral mechanical hyperalgesia, a bilateral increase in HCN2 expression and a unilateral increase in post‐translational SUMOylation. This suggests that enhanced HCN2 expression in L5 DRG is not sufficient for mechanical hyperalgesia in the early stages of inflammation and that hyper‐SUMOylation of HCN2 channels may also be necessary. SIGNIFICANCE: Nociceptor HCN2 channels mediate an increase in I(h) that is necessary for mechanical hyperalgesia in a CFA model of chronic pain, but the mechanisms producing the increase in nociceptor I(h) have not been resolved. The data presented here suggest that the increase in I(h) during the early stages of inflammation may be mediated by an increase in HCN2 protein expression and post‐translational SUMOylation. John Wiley and Sons Inc. 2020-06-14 2020-09 /pmc/articles/PMC7496191/ /pubmed/32446289 http://dx.doi.org/10.1002/ejp.1606 Text en © 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC® This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Forster, Lori A.
Jansen, Leslie‐Anne R.
Rubaharan, Myurajan
Murphy, Anne Z.
Baro, Deborah J.
Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
title Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
title_full Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
title_fullStr Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
title_full_unstemmed Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
title_short Alterations in SUMOylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
title_sort alterations in sumoylation of the hyperpolarization‐activated cyclic nucleotide‐gated ion channel 2 during persistent inflammation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496191/
https://www.ncbi.nlm.nih.gov/pubmed/32446289
http://dx.doi.org/10.1002/ejp.1606
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