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Alterations in SUMOylation of the hyperpolarization-activated cyclic nucleotide-gated ion channel 2 during persistent inflammation.
Eur J Pain. 2020 09; 24(8):1517-1536.EJ

Abstract

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, Ih . An HCN2-mediated increase in C-nociceptor Ih 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 Ih that is necessary for mechanical hyperalgesia in a CFA model of chronic pain, but the mechanisms producing the increase in nociceptor Ih have not been resolved. The data presented here suggest that the increase in Ih during the early stages of inflammation may be mediated by an increase in HCN2 protein expression and post-translational SUMOylation.

Authors+Show Affiliations

Department of Biology, Georgia State University, Atlanta, GA, USA. Neuroscience Institute, Georgia State University, Atlanta, GA, USA.Department of Biology, Georgia State University, Atlanta, GA, USA.Neuroscience Institute, Georgia State University, Atlanta, GA, USA.Neuroscience Institute, Georgia State University, Atlanta, GA, USA.Department of Biology, Georgia State University, Atlanta, GA, USA. Neuroscience Institute, Georgia State University, Atlanta, GA, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32446289

Citation

Forster, Lori A., et al. "Alterations in SUMOylation of the Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channel 2 During Persistent Inflammation." European Journal of Pain (London, England), vol. 24, no. 8, 2020, pp. 1517-1536.
Forster LA, Jansen LR, Rubaharan M, et al. Alterations in SUMOylation of the hyperpolarization-activated cyclic nucleotide-gated ion channel 2 during persistent inflammation. Eur J Pain. 2020;24(8):1517-1536.
Forster, L. A., Jansen, L. R., Rubaharan, M., Murphy, A. Z., & Baro, D. J. (2020). Alterations in SUMOylation of the hyperpolarization-activated cyclic nucleotide-gated ion channel 2 during persistent inflammation. European Journal of Pain (London, England), 24(8), 1517-1536. https://doi.org/10.1002/ejp.1606
Forster LA, et al. Alterations in SUMOylation of the Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channel 2 During Persistent Inflammation. Eur J Pain. 2020;24(8):1517-1536. PubMed PMID: 32446289.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alterations in SUMOylation of the hyperpolarization-activated cyclic nucleotide-gated ion channel 2 during persistent inflammation. AU - Forster,Lori A, AU - Jansen,Leslie-Anne R, AU - Rubaharan,Myurajan, AU - Murphy,Anne Z, AU - Baro,Deborah J, Y1 - 2020/06/14/ PY - 2020/01/13/received PY - 2020/04/28/revised PY - 2020/05/15/accepted PY - 2020/5/24/pubmed PY - 2021/1/26/medline PY - 2020/5/24/entrez SP - 1517 EP - 1536 JF - European journal of pain (London, England) JO - Eur J Pain VL - 24 IS - 8 N2 - 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, Ih . An HCN2-mediated increase in C-nociceptor Ih 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 Ih that is necessary for mechanical hyperalgesia in a CFA model of chronic pain, but the mechanisms producing the increase in nociceptor Ih have not been resolved. The data presented here suggest that the increase in Ih during the early stages of inflammation may be mediated by an increase in HCN2 protein expression and post-translational SUMOylation. SN - 1532-2149 UR - https://www.unboundmedicine.com/medline/citation/32446289/Alterations_in_SUMOylation_of_the_hyperpolarization_activated_cyclic_nucleotide_gated_ion_channel_2_during_persistent_inflammation_ L2 - https://doi.org/10.1002/ejp.1606 DB - PRIME DP - Unbound Medicine ER -