Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1

Sheng Wang, Sen Wang, Jamila Asgar, John Joseph, Jin Y. Ro, Feng Wei, James N Campbell, Man Kyo Chung

Research output: Contribution to journalArticle

Abstract

Capsaicin is an ingredient in spicy peppers that produces burning pain by activating transient receptor potential vanilloid 1 (TRPV1), a Ca2+-permeable ion channel in nociceptors. Capsaicin has also been used as an analgesic, and its topical administration is approved for the treatment of certain pain conditions. The mechanisms underlying capsaicin-induced analgesia likely involve reversible ablation of nociceptor terminals. However, the mechanisms underlying these effects are not well understood. To visualize TRPV1-lineage axons, a genetically engineered mouse model was used in which a fluorophore is expressed under the TRPV1 promoter. Using a combination of these TRPV1-lineage reporter mice and primary afferent cultures, we monitored capsaicin-induced effects on afferent terminals in real time. We found that Ca2+ influx through TRPV1 is necessary for capsaicin-induced ablation of nociceptive terminals. Although capsaicin-induced mitochondrial Ca2+ uptake was TRPV1-dependent, dissipation of the mitochondrial membrane potential, inhibition of the mitochondrial transition permeability pore, and scavengers of reactive oxygen species did not attenuate capsaicin-induced ablation. In contrast, MDL28170, an inhibitor of the Ca2+-dependent protease calpain, diminished ablation. Furthermore, overexpression of calpastatin, an endogenous inhibitor of calpain, or knockdown of calpain 2 also decreased ablation. Quantitative assessment of TRPV1-lineage afferents in the epidermis of the hind paws of the reporter mice showed that EGTA and MDL28170 diminished capsaicin-induced ablation. Moreover, MDL28170 prevented capsaicin-induced thermal hypoalgesia. These results suggest that TRPV1/Ca2+/calpain-dependent signaling plays a dominant role in capsaicin-induced ablation of nociceptive terminals and further our understanding of the molecular mechanisms underlying the effects of capsaicin on nociceptors.

Original languageEnglish (US)
Pages (from-to)8291-8303
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number20
DOIs
StatePublished - May 19 2017
Externally publishedYes

Fingerprint

Calpain
Capsaicin
Ablation
Nociceptors
vanilloid receptor subtype 1
Topical Administration
Pain
Fluorophores
Mitochondrial Membrane Potential
Egtazic Acid
Ion Channels
Epidermis
Analgesia
Axons
Analgesics
Reactive Oxygen Species
Peptide Hydrolases
Hot Temperature
Membranes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1. / Wang, Sheng; Wang, Sen; Asgar, Jamila; Joseph, John; Ro, Jin Y.; Wei, Feng; Campbell, James N; Chung, Man Kyo.

In: Journal of Biological Chemistry, Vol. 292, No. 20, 19.05.2017, p. 8291-8303.

Research output: Contribution to journalArticle

Wang, Sheng ; Wang, Sen ; Asgar, Jamila ; Joseph, John ; Ro, Jin Y. ; Wei, Feng ; Campbell, James N ; Chung, Man Kyo. / Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 20. pp. 8291-8303.
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AU - Wang, Sheng

AU - Wang, Sen

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AU - Wei, Feng

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