Modification of TRPV4 activity by acetaminophen
N-Acetyl-p-aminophenol (APAP/acetaminophen) is a widely used analgesic/antipyretic with weaker inhibitory effects on cyclooxygenase compared to those of non-steroidal anti-inflammatory drugs. The effect of APAP is mediated by its metabolites, N-arachidonoyl-phenolamine and N-acetyl-p-benzoquinone im...
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doaj-5737fee1a14f424d8ae20517602d5e1e2020-11-25T02:14:03ZengElsevierHeliyon2405-84402020-01-0161e03301Modification of TRPV4 activity by acetaminophenFumio Nakagawa0Sen Higashi1Eika Ando2Tomoko Ohsumi3Seiji Watanabe4Hiroshi Takeuchi5Division of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Kitakyushu, 803-8580, Japan; Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, 803-8580, JapanDivision of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, 803-8580, JapanDivision of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Kitakyushu, 803-8580, JapanDivision of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, 803-8580, JapanDivision of Dental Anesthesiology, Department of Control of Physical Functions, Kyushu Dental University, Kitakyushu, 803-8580, JapanDivision of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, 803-8580, Japan; Corresponding author.N-Acetyl-p-aminophenol (APAP/acetaminophen) is a widely used analgesic/antipyretic with weaker inhibitory effects on cyclooxygenase compared to those of non-steroidal anti-inflammatory drugs. The effect of APAP is mediated by its metabolites, N-arachidonoyl-phenolamine and N-acetyl-p-benzoquinone imine, which activate transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or cannabinoid receptor type 1. However, the exact molecular mechanism underlying the cellular actions of APAP remains unclear. Recently, we observed that APAP promotes cell migration through TRPV4; in this study, we examined the effect of APAP on Ca2+-channel activity of TRPV4.In the rat cell line PC12 expressing TRPV4, GSK1016790A (GSK), a TRPV4 agonist, stimulated an increase in [Ca2+]i; these effects were abrogated by HC-067047 treatment. This GSK-induced Ca2+ entry through TRPV4 was inhibited by APAP in a dose-dependent manner, whereas APAP alone did not affect [Ca2+]i. The specificity of the effect of APAP on TRPV4 was further confirmed using HeLa cells, which lack endogenous TRPV4 but stably express exogenous TRPV4 (HeLa-mTRPV4). GSK-induced [Ca2+]i elevation was only observed in HeLa-mTRPV4 cells compared to that in the control HeLa cells, indicating the specific action of GSK on TRPV4. APAP dose-dependently suppressed this GSK-induced Ca2+ entry in HeLa-mTRPV4. However, it is unlikely that the metabolites of APAP were involved in these effects as the reaction in this study was rapid.The results suggest that APAP suppresses the newly identified target TRPV4 without being metabolized and exerts antipyretic/analgesic and/or other effects on TRPV4-related phenomena in the body. The effect of APAP on TRPV4 was opposite to that on TRPV1 or TRPA1, as the latter is activated by APAP.http://www.sciencedirect.com/science/article/pii/S2405844020301468ElectrophysiologyMolecular neuroscienceCell cultureMembranePhysiologyNervous system |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fumio Nakagawa Sen Higashi Eika Ando Tomoko Ohsumi Seiji Watanabe Hiroshi Takeuchi |
spellingShingle |
Fumio Nakagawa Sen Higashi Eika Ando Tomoko Ohsumi Seiji Watanabe Hiroshi Takeuchi Modification of TRPV4 activity by acetaminophen Heliyon Electrophysiology Molecular neuroscience Cell culture Membrane Physiology Nervous system |
author_facet |
Fumio Nakagawa Sen Higashi Eika Ando Tomoko Ohsumi Seiji Watanabe Hiroshi Takeuchi |
author_sort |
Fumio Nakagawa |
title |
Modification of TRPV4 activity by acetaminophen |
title_short |
Modification of TRPV4 activity by acetaminophen |
title_full |
Modification of TRPV4 activity by acetaminophen |
title_fullStr |
Modification of TRPV4 activity by acetaminophen |
title_full_unstemmed |
Modification of TRPV4 activity by acetaminophen |
title_sort |
modification of trpv4 activity by acetaminophen |
publisher |
Elsevier |
series |
Heliyon |
issn |
2405-8440 |
publishDate |
2020-01-01 |
description |
N-Acetyl-p-aminophenol (APAP/acetaminophen) is a widely used analgesic/antipyretic with weaker inhibitory effects on cyclooxygenase compared to those of non-steroidal anti-inflammatory drugs. The effect of APAP is mediated by its metabolites, N-arachidonoyl-phenolamine and N-acetyl-p-benzoquinone imine, which activate transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or cannabinoid receptor type 1. However, the exact molecular mechanism underlying the cellular actions of APAP remains unclear. Recently, we observed that APAP promotes cell migration through TRPV4; in this study, we examined the effect of APAP on Ca2+-channel activity of TRPV4.In the rat cell line PC12 expressing TRPV4, GSK1016790A (GSK), a TRPV4 agonist, stimulated an increase in [Ca2+]i; these effects were abrogated by HC-067047 treatment. This GSK-induced Ca2+ entry through TRPV4 was inhibited by APAP in a dose-dependent manner, whereas APAP alone did not affect [Ca2+]i. The specificity of the effect of APAP on TRPV4 was further confirmed using HeLa cells, which lack endogenous TRPV4 but stably express exogenous TRPV4 (HeLa-mTRPV4). GSK-induced [Ca2+]i elevation was only observed in HeLa-mTRPV4 cells compared to that in the control HeLa cells, indicating the specific action of GSK on TRPV4. APAP dose-dependently suppressed this GSK-induced Ca2+ entry in HeLa-mTRPV4. However, it is unlikely that the metabolites of APAP were involved in these effects as the reaction in this study was rapid.The results suggest that APAP suppresses the newly identified target TRPV4 without being metabolized and exerts antipyretic/analgesic and/or other effects on TRPV4-related phenomena in the body. The effect of APAP on TRPV4 was opposite to that on TRPV1 or TRPA1, as the latter is activated by APAP. |
topic |
Electrophysiology Molecular neuroscience Cell culture Membrane Physiology Nervous system |
url |
http://www.sciencedirect.com/science/article/pii/S2405844020301468 |
work_keys_str_mv |
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