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Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways

1
Division of Cancer Pathophysiology, National Cancer Research Institute, Tokyo 104-0045, Japan
2
Emergency Life-Saving Technique Academy of Tokyo (ELSTA TOKYO), Hachioji-shi, Tokyo 192-0364, Japan
3
Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, Tochigi 329-0498, Japan
4
Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
5
Department of Anesthesiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
6
Translational Research Center, Research Institute of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan
7
Division of Supportive Care Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104-0045, Japan
8
Innovation Center for Supportive, Palliative and Psychosocial Care, National Cancer Center, Tokyo 104-0045, Japan
9
Department of Comprehensive Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(13), 3271; https://doi.org/10.3390/ijms20133271
Received: 14 June 2019 / Revised: 1 July 2019 / Accepted: 2 July 2019 / Published: 3 July 2019
(This article belongs to the Section Biochemistry)
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Abstract

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. View Full-Text
Keywords: carboplatin; CIPN; TRPA1; cAMP; PKA; AKAP carboplatin; CIPN; TRPA1; cAMP; PKA; AKAP
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Miyano, K.; Shiraishi, S.; Minami, K.; Sudo, Y.; Suzuki, M.; Yokoyama, T.; Terawaki, K.; Nonaka, M.; Murata, H.; Higami, Y.; Uezono, Y. Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways. Int. J. Mol. Sci. 2019, 20, 3271.

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