Modification of TRPV4 activity by acetaminophen

Abstract

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 Ca 2þ-channel activity of TRPV4. In the rat cell line PC12 expressing TRPV4, GSK1016790A (GSK), a TRPV4 agonist, stimulated an increase in [Ca 2þ ] i ; these effects were abrogated by HC-067047 treatment. This GSK-induced Ca 2þ entry through TRPV4 was inhibited by APAP in a dose-dependent manner, whereas APAP alone did not affect [Ca 2þ ] 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 [Ca 2þ ] 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 dosedependently suppressed this GSK-induced Ca 2þ 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.

Paracetamol – An old drug with new mechanisms of action

“…have revealed that the Ca2þ channel activity of TRPV4 is inhibited by paracetamol. 146 The effects of paracetamol on TRPV4 differed from the action on TRPV1 and TRPA1 reported previously. Firstly, paracetamol metabolites are unlikely to be involved in these effects,…”

“…were activated by paracetamol in vivo. 146 However, the molecular mechanism of paracetamol activity on the Ca2þ channel activity of TRPV4 is complex, as it is not known whether it works outside or inside the cell membrane of theTRPV4 Ca2þ channel. Finally, inhibition of Ca2þ entry into cells via TRPV4 may also contribute to the clinical effects induced by paracetamol, which has not been reported previously as a paracetamol target.…”

“…Finally, inhibition of Ca2þ entry into cells via TRPV4 may also contribute to the clinical effects induced by paracetamol, which has not been reported previously as a paracetamol target. 146 This is suggested by studies in which mice with TRPV4 genetic deficiency had reduced susceptibility to stimuli that were harmful to acid and pressure and TRPV4 expression occurs, among others, in the peripheral nerve endings of sensory ganglia. 146 Furthermore, the sensitization of TRPV4 by PGE 2 was postulated to be involved in the hyperalgesic response to heat, pressure stimulation at the site of inflammation, and hypotonic pressure.…”

“…146 This is suggested by studies in which mice with TRPV4 genetic deficiency had reduced susceptibility to stimuli that were harmful to acid and pressure and TRPV4 expression occurs, among others, in the peripheral nerve endings of sensory ganglia. 146 Furthermore, the sensitization of TRPV4 by PGE 2 was postulated to be involved in the hyperalgesic response to heat, pressure stimulation at the site of inflammation, and hypotonic pressure. 147 There are also reports demonstrating that TRPV4 is involved in the induction of pulmonary oedema associated with heart failure and is related with cardiovascular homeostasis.…”

“…148 Therefore, it would be interesting not only to explain the role of TRPV4 in the analgesic/antipyretic effect of paracetamol, but also to investigate the effect of paracetamol used for other purposes such as cardiovascular homeostasis. 146,149…”