Fibroblast growth factor 13 stabilizes microtubules to promote Na+ channel function in nociceptive DRG neurons and modulates inflammatory pain

Qiong Wang; Jing Yang; Handong Wang; Bin Shan; Chengyu Yin; Hang Yu; Xuerou Zhang; Zishan Dong; Yulou Yu; Ran Zhao; Boyi Liu; Hailin Zhang; Chuan Wang

doi:10.1016/j.jare.2020.12.009

Fibroblast growth factor 13 stabilizes microtubules to promote Na⁺ channel function in nociceptive DRG neurons and modulates inflammatory pain

J Adv Res. 2020 Dec 17:31:97-111. doi: 10.1016/j.jare.2020.12.009. eCollection 2021 Jul.

Authors

Qiong Wang¹, Jing Yang², Handong Wang³, Bin Shan⁴, Chengyu Yin⁵, Hang Yu³, Xuerou Zhang³, Zishan Dong¹, Yulou Yu¹, Ran Zhao¹, Boyi Liu⁵, Hailin Zhang¹, Chuan Wang¹

Affiliations

¹ Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
² Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China.
³ College of Basic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
⁴ Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050017, China.
⁵ Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China.

Abstract

Introduction: Fibroblast growth factor homologous factors (FHFs), among other fibroblast growth factors, are increasingly found to be important regulators of ion channel functions. Although FHFs have been link to several neuronal diseases and arrhythmia, its role in inflammatory pain still remains unclear.

Objectives: This study aimed to investigate the role and mechanism of FGF13 in inflammatory pain.

Methods: Fgf13 conditional knockout mice were generated and CFA-induced chronic inflammatory pain model was established to measure the pain threshold. Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of FGF13 in CFA-induced inflammatory pain. Whole-cell patch clamp recording was used to record the action potential firing properties and sodium currents of DRG neurons.

Results: Conditional knockout of Fgf13 in dorsal root ganglion (DRG) neurons (Fgf13^-/Y) led to attenuated pain responses induced by complete Freund's adjuvant (CFA). FGF13 was expressed predominantly in small-diameter DRG neurons. CFA treatment resulted in an increased expression of FGF13 proteins as well as an increased excitability in nociceptive DRG neurons which was inhibited when FGF13 was absent. The role of FGF13 in neuronal excitability of DRG was linked to its modulation of voltage-gated Na⁺ channels mediated by microtubules. Overexpression of FGF13, but not FGF13 mutant which lacks the ability to bind and stabilize microtubules, rescued the decreased neuronal excitability and Na⁺ current density in DRG neurons of Fgf13^-/Y mice.

Conclusion: This study revealed that FGF13 could stabilize microtubules to modulate sodium channel function in DRG neurons and modulate inflammatory pain. This study provides a novel mechanism for FGF13 modulation of sodium channel function and suggests that FGF13 might be a novel target for inflammatory pain treatment.

Keywords: DRG; Fibroblast growth factor 13; Inflammatory pain; Microtubules; Na+ channel.

Publication types

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

MeSH terms

Action Potentials
Animals
Chronic Pain / genetics
Chronic Pain / metabolism*
Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / metabolism*
Freund's Adjuvant / adverse effects
Ganglia, Spinal / metabolism*
Inflammation / genetics
Inflammation / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microtubules / metabolism*
Nociceptors / metabolism*
Pain Threshold
Patch-Clamp Techniques / methods
Polymerase Chain Reaction / methods
Sodium / metabolism
Sodium Channels / metabolism*

Substances

Sodium Channels
fibroblast growth factor 13
Fibroblast Growth Factors
Freund's Adjuvant
Sodium