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

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.

Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

“…Given that EA could influence multiple signaling pathways, including β-endorphins ( Han, 2003 ), cannabinoid CB2 receptors, and adenosine A1 receptor ( Goldman et al, 2010 ), the 5-HT 7 R-associated PKA and ERK 1 / 2 phosphorylation through Gαs-cAMP signaling is likely only one of the key factors involved in EA’s maintenance of antihyperalgesic effects. Moreover, cAMP interacts with several other proteins in addition to PKA and ERK 1 / 2 , including ROS ( Gu et al, 2018 ), NF-κB ( Wang J. et al, 2018 ), and AKAP ( Miyano et al, 2019 ), which might also be involved in the maintenance of the antihyperalgesic effects by EA. Next, we will use naloxone to block opioid receptors, or DPCPX to block A1 receptors, so as to exclude the effect of other factors on EA antihyperalgesia, and then confirm the role of 5-HT 7 R.…”

Proximal C-Terminus Serves as a Signaling Hub for TRPA1 Channel Regulation via Its Interacting Molecules and Supramolecular Complexes

“…AKAP directly interacts with TRPA1 (Zhang et al, 2008), but it also engages in multiple protein-protein interactions including Ca 2+ -CaM (Faux and Scott, 1997;Patel et al, 2017). Given the recently proposed importance of the AKAP-PKA pathway in TRPA1-mediated mechanical allodynia and cold hyperalgesia (Brackley et al, 2017;Miyano et al, 2019), it would be particularly important to test the hypothesis that AKAP may serve as a molecular hub that contributes to the specificity and efficiency of the cellular signaling network regulating TRPA1 under various physiological or pathophysiological conditions (Figures 2A-D).…”

Intravenous administration of human mesenchymal stem cells derived from adipose tissue and umbilical cord improves neuropathic pain via suppression of neuronal damage and anti-inflammatory actions in rats

“…To evaluate pain behaviors, the von Frey and dynamic weight bearing (DWB) tests were performed. The von Frey test was performed to assess mechanical threshold, as previously described [ 14 ]. According to the procedure by Chaplan et al [ 15 ], the 50% paw withdrawal threshold was measured using the up-down method with a von Frey filament (0.01–15.0 g).…”