Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways.
Kanako MiyanoSeiji ShiraishiKoichiro MinamiYuka SudoMasami SuzukiToru YokoyamaKiyoshi TerawakiMiki NonakaHiroaki MurataYoshikazu HigamiYasuhito UezonoPublished in: International journal of molecular sciences (2019)
Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+]i); however, carboplatin pretreatment enhanced the increase in [Ca2+]i induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+]i and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+]i induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.
Keyphrases
- protein kinase
- high glucose
- phase ii study
- neuropathic pain
- diabetic rats
- endothelial cells
- drug induced
- squamous cell carcinoma
- spinal cord
- emergency department
- chronic pain
- immune response
- oxidative stress
- radiation therapy
- spinal cord injury
- binding protein
- open label
- protein protein
- locally advanced
- cerebral ischemia
- risk assessment
- cell proliferation
- nuclear factor
- reactive oxygen species
- subarachnoid hemorrhage
- pluripotent stem cells
- human health