Signaling Pathways Relevant to Nerve Growth Factor-induced Upregulation of Transient Receptor Potential M8 Expression

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Keiji Ibata, Jin Nakahara, Toshihiko Shimizu, Haruki Toriumi, Michisuke Yuzaki, Norihiro Suzuki

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that primarily detects the innocuous cold. In pathological conditions, TRPM8 plays a role in the development of cold hyperalgesia/allodynia. Nerve growth factor (NGF) is an important mediator involved in various pain disorders. In the present study, the NGF-TrkA pathway increased TRPM8 expression by stabilizing TRPM8 mRNA through the actions of phosphatidylinositol 3-kinase and p38 MAP kinase. Moreover, c-Jun N-terminal kinase and Src tyrosine kinase were identified as a positive and negative regulator of TRPM8 expression, respectively, via post-transcriptional mechanisms independent of mRNA stabilization. PTEN activity was found to increase protein TRPM8 expression. Calcium imaging confirmed that NGF induced TRPM8 functional upregulation. Time-lapse fluorescence microscopic analysis and a cell fractionation assay revealed that NGF promoted the trafficking of TRPM8 to the plasma membrane. In the presence of NGF, lysosome-associated membrane protein-2 (LAMP-2) was localized to TRPM8-positive dot-like and linear structures, the latter of which were observed in the periphery of the cytoplasm. It was inferred that LAMP-2 was involved in the vesicular transport of TRPM8. Pharmacological blockade of the proteasome with MG132 led to a further increase in NGF-induced TRPM8 expression, indicating that the proteasome system played a pivotal role in the degradation of TRPM8. Our findings provide novel insight into the signaling pathways involved in NGF-mediated TRPM8 upregulation and its reversion to the normal state.

Original languageEnglish
Pages (from-to)178-188
Number of pages11
Publication statusPublished - 2017 Dec 26


  • inflammatory pain
  • nerve growth factor (NGF)
  • neuropathic pain
  • proteasome
  • receptor trafficking
  • transient receptor potential M8 (TRPM8)

ASJC Scopus subject areas

  • General Neuroscience


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