Signaling Pathways Relevant to Nerve Growth Factor-induced Upregulation of Transient Receptor Potential M8 Expression. (26th December 2017)

• Record Type: Journal Article
• Authors: Kayama, Yohei; Shibata, Mamoru; Takizawa, Tsubasa; Ibata, Keiji; Nakahara, Jin; Shimizu, Toshihiko; Toriumi, Haruki; Yuzaki, Michisuke; Suzuki, Norihiro
• Is Part Of: Neuroscience. Volume 367(2017)
• Page Start: 178
• Page End: 188
• Publication Date: 2017-12-26
• Subjects: 4-OHT 4-hydroxytamoxifen -- ANOVA analysis of variance -- DAG diacylglycerol -- DMSO dimethyl sulfoxide -- DRG dorsal root ganglion -- EmGFP Emerald green fluorescent protein -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- IP3 inositol 1, 4, 5-trisphosphate -- JNK c-Jun N-terminal kinase -- KO knockout -- LAMP-2 lysosome-associated membrane protein-2 -- MAPK mitogen-activated protein kinase -- MEK mitogen-activated protein kinase/extracellular signal-activated kinase kinase -- NGF nerve growth factor -- PBS phosphate-buffered saline -- PI3K phosphatidylinositol 3-kinase -- PKC protein kinase C -- PLC phospholipase C -- PtdIns(4, 5)P2 phosphatidylinositol 4, 5-bisphosphate -- PTEN phosphatase and Tensin homolog deleted from Chromosome 10 -- Src sarcoma-family kinase -- TG trigeminal ganglion -- TRPM8 transient receptor potential melastatin 8 -- TRPV1 transient receptor potential vanilloid 1 -- VAMP7 vesicle-associated membrane protein 7; transient receptor potential M8 (TRPM8) -- nerve growth factor (NGF) -- receptor trafficking -- neuropathic pain -- inflammatory pain -- proteasome; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2017.10.037
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: The NGF-TrkA signaling pathway promotes whole-cell and cell-surface TRPM8 expression accompanied by functional upregulation. Several kinases and the proteasome are involved in the regulatory mechanisms of TRPM8 expression levels. NGF treatment enhances the colocalization of TRPM8 with LAMP-2. Abstract: 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.