Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis
| Autor: | You Wan, Guo-Gang Xing, Bo-Heng Liu, Yue Yang, Hong-Bo Jing, Zi-Run Jin, Jie Cai, Ya-Jing Liang, Ling-Yu Liu, Song Li, Hong-Yan Zhao |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine Potassium Channels Sensory Receptor Cells Bone Neoplasms Mammary Neoplasms Animal Pharmacology Biochemistry Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Dorsal root ganglion Cell Line Tumor Ganglia Spinal medicine Animals Neoplasm Metastasis RNA Small Interfering Molecular Biology Gene knockdown Behavior Animal business.industry Calcineurin Gene Expression Profiling Intracellular Signaling Peptides and Proteins Nociceptors Bone metastasis NFAT Cancer Pain Cell Biology medicine.disease Vascular Endothelial Growth Factor Receptor-2 Potassium channel Rats Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Nociception Neuropathic pain Potassium Calcium Female Peptides business 030217 neurology & neurosurgery |
| Zdroj: | Science Signaling. 11 |
| ISSN: | 1937-9145 1945-0877 |
| Popis: | Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|