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

2019 ◽  
Vol 20 (13) ◽  
pp. 3271 ◽  
Author(s):  
Kanako Miyano ◽  
Seiji Shiraishi ◽  
Koichiro Minami ◽  
Yuka Sudo ◽  
Masami Suzuki ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Adenosine Monophosphate ◽  
Anchoring Protein ◽  
Cold Hyperalgesia ◽  
Transient Receptor ◽  
Kinase A

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.

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

2019 ◽  
Author(s):  
Kanako Miyano ◽  
Seiji Shiraishi ◽  
Koichiro Minami ◽  
Yuka Sudo ◽  
Masami Suzuki ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Adenosine Monophosphate ◽  
Anchoring Protein ◽  
Cold Hyperalgesia ◽  
Transient Receptor ◽  
Kinase A

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 involved not only 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 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.

Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner

Pain ◽  
2013 ◽  
Vol 154 (4) ◽  
pp. 598-608 ◽  
Author(s):  
Viola Spahn ◽  
Oliver Fischer ◽  
Jeannette Endres-Becker ◽  
Michael Schäfer ◽  
Christoph Stein ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Opioid Withdrawal ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor ◽  
Kinase A

scholarly journals Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A–mediated phosphorylation

2018 ◽  
Vol 293 (14) ◽  
pp. 5307-5322 ◽  
Author(s):  
Sheng Cao ◽  
Andriy Anishkin ◽  
Natalya S. Zinkevich ◽  
Yoshinori Nishijima ◽  
Ankush Korishettar ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor ◽  
Kinase A

scholarly journals PP2B/calcineurin-mediated desensitization of TRPV1 does not require AKAP150

2010 ◽  
Vol 432 (3) ◽  
pp. 549-556 ◽  
Author(s):  
Elaine D. Por ◽  
Bret K. Samelson ◽  
Sergei Belugin ◽  
Armen N. Akopian ◽  
John D. Scott ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trigeminal Ganglia ◽  
Functional Studies ◽  
Protein Phosphatase 2B ◽  
Anchoring Protein ◽  
Pkc Protein Kinase C ◽  
Transient Receptor

Activation of protein kinases and phosphatases at the plasma membrane often initiates agonist-dependent signalling events. In sensory neurons, AKAP150 (A-kinase-anchoring protein 150) orientates PKA (protein kinase A), PKC (protein kinase C) and the Ca2+/calmodulin-dependent PP2B (protein phosphatase 2B, also known as calcineurin) towards membrane-associated substrates. Recent evidence indicates that AKAP150-anchored PKA and PKC phosphorylate and sensitize the TRPV1 (transient receptor potential subfamily V type 1 channel, also known as the capsaicin receptor). In the present study, we explore the hypothesis that an AKAP150-associated pool of PP2B catalyses the dephosphorylation and desensitization of TRPV1. Biochemical, electrophysiological and cell-based experiments indicate that PP2B associates with AKAP150 and TRPV1 in cultured TG (trigeminal ganglia) neurons. Gene silencing of AKAP150 reduces basal phosphorylation of TRPV1. However, functional studies in neurons isolated from AKAP150−/− mice indicate that the anchoring protein is not required for pharmacological desensitization of TRPV1. Behavioural analysis of AKAP150−/− mice further support this notion, demonstrating that agonist-stimulated desensitization of TRPV1 is sensitive to PP2B inhibition and does not rely on AKAP150. These findings allow us to conclude that pharmacological desensitization of TRPV1 by PP2B may involve additional regulatory components.

scholarly journals Protein Kinase A–dependent Spinal α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionate–receptor Trafficking Mediates Capsaicin-induced Colon-Urethra Cross-organ Reflex Sensitization

2011 ◽  
Vol 114 (1) ◽  
pp. 70-83 ◽  
Author(s):  
Hsien-Yu Peng ◽  
Chao-Hsiang Chang ◽  
Shin-Jei Tsai ◽  
Cheng-Yuan Lai ◽  
Kwong-Chung Tung ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Membrane Fraction ◽  
Cyclic Adenosine Monophosphate ◽  
Fold Increase ◽  
Adenosine Monophosphate ◽  
Human Thyroid ◽  
Anchoring Protein ◽  
Ampar Trafficking ◽  
Kinase A

Background Intracellular redistribution of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate receptors (AMPARs) is known to be induced by natural painful stimulation. We tested the hypothesis that that protein kinase A (PKA)-dependent AMPAR trafficking underlies the development of N-methyl-d-aspartate receptor-mediated cross-organ sensitization in vivo. Methods We recorded urethra reflex activity and analyzed immunoblotting of lumbosacral (L6-S2) dorsal horn (DH) tissue obtained from animal preparations after intrathecal 8-bromo-cyclic adenosine monophosphate injection or intracolonic instillation with 8-methyl-N-vanillyl-trans-6-nonenamide (capsaicin). Results Intrathecal 8-bromo-cyclic adenosine monophosphate (300 μM, 10 μl) induced reflex potentiation (81.85 ± 22.21 spikes/stimulation) and increased the number of AMPAR Glu receptor 1 subunits in the membrane fraction of DH (1.8-fold increase vs. control). This process was prevented by pretreatment with the PKA inhibitor N-[2- ((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide(10 μM, 10 μl, 2.7 ± 0.8 [mean ± SE] spikes/stimulation) and human thyroid A kinase-anchoring protein (10 μM, 10 μl, 11.5 ± 4.8 spikes/stimulation), an inhibitor of PKA and PKA-A kinase-anchoring protein interactions. Intracolonic capsaicin instillation sensitized the urethra reflex (137.2 ± 62.4 spikes/stimulation) and, relative to control, simultaneously provoked an increase (2.9-fold) in the membrane fraction and a decrease (0.9-fold) in the cytosolic fraction of Glu receptor 1 subunits in DH. Inhibition of PKA activity and disruption of PKA-A kinase-anchoring protein interaction in the DH (2.0 ± 0.6 and 16.7 ± 2.8 spikes/stimulation, respectively) are sufficient to prevent capsaicin-dependent reflex sensitization and AMPAR trafficking in the membrane fraction (0.6- and 0.5-fold increase capsaicin). Conclusion Delivery of AMPAR-containing Glu receptor 1 subunits to the membranes of lumbosacral DH neurons through a PKA-dependent pathway contributes to noxious stimulation-induced synaptic strengthening, which plays roles in colon-urethra reflex sensitization.

scholarly journals TRPC6-Mediated Ca2+ Signaling is Required for Hypoxia-Induced Autophagy in Human Podocytes

2018 ◽  
Vol 48 (4) ◽  
pp. 1782-1792 ◽  
Author(s):  
Tianrong Ji ◽  
Chengwei Zhang ◽  
Linlin Ma ◽  
Qin Wang ◽  
Li Zou ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
Hypoxic Conditions ◽  
Transient Receptor ◽  
Ca2 Channels

Background/Aims: Intracellular Ca2+ signaling plays an important role in the regulation of autophagy. However, very little is known about the role of Ca2+ influx, which is induced by plasma membrane Ca2+ channels. Our previous study showed that transient receptor potential canonical channel-6 (TRPC6), a major Ca2+ influx pathway in podocytes, was activated by hypoxia. Here, we investigated whether TRPC6 is involved in hypoxia-induced autophagy in cultured human podocytes. Methods: In the present study, an immortalized human podocyte cell line was used. Fluo-3 fluorescence was utilized to determine intracellular Ca2+ concentration ([Ca2+]i), and western blotting was used to measure autophagy and protein expression. Results: We found that blockade TRPC6 by using either TRPC6 siRNA or a TRPC6 blocker attenuated hypoxia-induced autophagy, while enhancement of TRPC6 activity with a TRPC6 activator enhanced hypoxia-induced autophagy. Furthermore, TRPC6-dependent Ca2+ signaling is responsible for hypoxia-induced autophagy since both an intracellular and extracellular Ca2+ chelator abolished hypoxia-induced autophagy. Moreover, we found that blockade of TRPC6 by using either TRPC6 siRNA or a TRPC6 blocker decreased the expression of adenosine monophosphate-activated protein kinase (AMPK), an important signaling molecule in Ca2+-dependent autophagy activation, which is activated under hypoxic conditions. These data suggest that the involvement of TRPC6 in hypoxia-induced autophagy is associated with AMPK signaling. Conclusion: TRPC6 is essential for hypoxia-induced autophagy in podocytes.

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