- Email: [email protected]
Significance of TRP channels in oxidative stress
European Journal of Pharmacology xx (xxxx) xxxx–xxxx
Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Significance of TRP channels in oxidative stress Shinichiro Yamamoto, Shunichi Shimizu
⁎
Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
A R T I C L E I N F O
A BS T RAC T
Keywords: TRP channels TRPM2 TRPA1 Reactive oxygen species Oxidative stress
Reactive oxygen species induce oxidative stress, leading to cell damage, but also function as signal transduction molecules. Transient receptor potential (TRP) channels have been attracting increasing attention as Ca2+permeable channels that sense environmental changes. The members of one class of TRP channels have emerged as reactive oxygen species sensors. The significance of Ca2+ signaling induced by the activation of reactive oxygen species-sensitive TRP channels under pathological conditions is currently being elucidated. The selective inhibition of reactive oxygen species-sensitive TRP channels represents a future challenge that may lead to new therapeutic strategies for the suppression of reactive oxygen species-related diseases.
1. Reactive oxygen species-sensitive TRP channels Transient receptor potential (TRP) channels have been divided into six subfamilies (C, V, M, P, ML, and A) (Clapham, 2003). TRPM2, TRPC5, TRPV1, and TRPA1 have been identified as reactive oxygen species-sensitive Ca2+-permeable channels. The activation of TRPM2 is triggered by ADP-ribose binding to the NudT9-H domain in its Cterminus (Perraud et al., 2001). We previously reported that the activation of TRPM2 is triggered by reactive oxygen species such as hydrogen peroxide (H2O2) (Hara et al., 2002). Reactive oxygen speciesinduced TRPM2 activation was also found to be triggered by the production of ADP-ribose in nuclei via poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase pathways (Fonfria et al., 2004) (Fig. 1). We recently demonstrated that H2O2-induced TRPM2 activation was mediated through the hydroxyl radical, which is produced by the reaction of H2O2 with intracellular Fe2+ (Fenton reaction) (Ishii et al., 2006; Shimizu et al., 2015). On the other hand, TRPC5, TRPV1, and TRPA1 are activated by reactive oxygen species through oxidative modifications to cysteine residues (Yoshida et al., 2006; Takahashi et al., 2008). The sensitivity of TRPA1 to reactive oxygen species is the greatest among the TRP channels. Cysteine residues on the poreforming region located within the plasma membrane and cytoplasmic N-terminal region are considered to be essential for the reactive oxygen species-induced activation of TRPC5/TRPV1 and TRPA1, respectively (Fig. 1). The activation of TRPA1 by H2O2 appears to be mediated by H2O2-derived hydroxyl radicals (Andersson et al., 2008) (Fig. 1). Since the hydroxyl radical is membrane impermeable, the activation of TRPV1 and TRPC5 may be triggered by H2O2 rather than the hydroxyl radical. The hydroxyl radical is more reactive than H2O2. TRPA1 rather
⁎
than TRPC5 and TRPV1 has been suggested to function as an oxidative stress sensor. Under pathological conditions such as inflammatory diseases and ischemia-reperfusion, various cells produce a large amount of reactive oxygen species (Dröge, 2002; Lambeth, 2004). Ca2+ influx via reactive oxygen species-sensitive TRP channels under pathological conditions has been shown to contribute to the aggravation of these diseases. 2. Pathological roles of TRPA1 Pungent compounds such as allyl isothiocyanate in mustard oil and noxious cold stimuli trigger the activation of TRPA1 (Story et al., 2003; Jordt et al., 2004), suggesting that TRPA1 functions as a nociceptive receptor. TRPA1 also functions as an O2 sensor, which plays an important role in maintaining O2 homeostasis (Takahashi et al., 2011). A previous study demonstrated that TRPA1 expressed in sensory neurons mediated neuropeptide release and chemokine production in the airways, and these are responsible for the aggravation of asthma (Caceres et al., 2009). Asthma is an inflammatory disease, and reactive oxygen species also function as mediators for the aggravation of symptoms (Henricks and Nijkamp, 2001). Therefore, TRPA1 is considered to be a sensor of oxidative stress and has been implicated in inflammatory diseases. 3. Pathological roles of TRPM2 Previous studies have indicated that the activation of TRPM2 in response to reactive oxygen species participates in the aggravation of inflammatory diseases. Ca2+ influxes through TRPM2 in monocytes/
Corresponding author. E-mail address: [email protected] (S. Shimizu).
http://dx.doi.org/10.1016/j.ejphar.2016.11.007 Received 22 August 2016; Received in revised form 20 October 2016; Accepted 2 November 2016 Available online xxxx 0014-2999/ © 2016 Elsevier B.V. All rights reserved.
Please cite this article as: Yamamoto, S., European Journal of Pharmacology (2016), http://dx.doi.org/10.1016/j.ejphar.2016.11.007
European Journal of Pharmacology xx (xxxx) xxxx–xxxx
S. Yamamoto, S. Shimizu
TRPM2
TRPA1
TRPV1 TRPC5 SH HS
NudT9-H
NudT9-H
HS
ADP-ribose NAD+ PARP PARG poly(ADP-ribose) neucleus
trans membrane
SH
OH fenton reaction
H2O2
PARG: poly(ADP-ribose) glycohydrolase PARP: poly(ADP-ribose) polymerase
Fig. 1. Differences in reactive oxygen species-induced activation mechanisms among reactive oxygen species-sensitive TRP channels.
References
macrophages and alveolar epithelial cells induce the production of cytokines and activation of NLRP3 inflammasomes, which contribute to the aggravation of inflammatory diseases (Yamamoto et al., 2008; Haraguchi et al., 2012; Zhong et al., 2013; Yonezawa et al., 2016). TRPM2 also plays important roles in host defense responses through innate immunoresponses such as monocyte activation and cytokine production (Knowles et al., 2011). Therefore, Trpm2 KO mice are more susceptible to bacterial infections. Reactive oxygen species production during ischemia-reperfusion also triggers the activation of TRPM2, which participates in brain, heart, and kidney ischemia-reperfusion injury (Hiroi et al., 2013; Shimizu et al., 2013; Gao et al., 2014; Gelderblom et al., 2014), whereas findings on heart ischemia-reperfusion injury have been controversial (Miller et al., 2013, 2014; Hoffman et al., 2015). Additionally, TRPM2 has been shown to contribute to the development of acetaminophen-induced liver injury, radiation-induced tissue damage, and Alzheimer's disease, in which oxidative stress is accelerated (Liu et al., 2013; Kheradpezhouh et al., 2014; Park et al., 2014; Ostapchenko et al., 2015).
Andersson, D.A., et al., 2008. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J. Neurosci. 28, 2485–2494. Caceresa, A.I., et al., 2009. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Natl. Acad. Sci. USA 106, 9099–9104. Clapham, D.E., 2003. TRP channels as cellular sensors. Nature 426, 517–524. Dröge, W., 2002. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95. Fonfria, E., et al., 2004. TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br. J. Pharmacol. 143, 186–192. Gao, G., et al., 2014. TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1. J. Clin. Invest. 124, 4989–5001. Gelderblom, M., et al., 2014. Transient receptor potential melastatin subfamily member 2 cation channel regulates detrimental immune cell invasion in ischemic stroke. Stroke 45, 3395–3402. Hara, Y., et al., 2002. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol. Cell 9, 163–173. Haraguchi, K., et al., 2012. TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice. J. Neurosci. 32, 3931–3941. Henricks, P.A., Nijkamp, F.P., 2001. Reactive oxygen species as mediators in asthma. Pulm. Pharmacol. Ther. 14, 409–420. Hiroi, T., et al., 2013. Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischemia/reperfusion injury. Cardiovasc. Res. 97, 271–281. Hoffman, N.E., et al., 2015. Ca2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am. J. Physiol. Heart Circ. Physiol. 308, H637–H650. Ishii, M., et al., 2006. Intracellular-produced hydroxyl radical mediates H2O2-induced Ca2+ influx and cell death in rat beta-cell line RIN-5F. Cell Calcium 39, 487–494. Jordt, S.E., et al., 2004. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265. Kheradpezhouh, E., Barritt, G.J., Rychkov, G.Y., 2016. Cumin inhibits activation of TRPM2 channels in rat hepatocytes. Redox Biol. 7, 1–7. Kheradpezhouh, E., et al., 2014. TRPM2 channels mediate acetaminophen-induced liver damage. Proc. Natl. Acad. Sci. USA 111, 3176–3181. Knowles, H., et al., 2011. Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. Proc. Natl. Acad. Sci. USA 108, 11578–11583. Lambeth, J.D., 2004. NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189. Leamy, A.W., et al., 2011. Curcumin ((E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-3,5-dione) activates and desensitizes the nociceptor ion channel TRPA1. Neurosci. Lett. 503, 157–162. Liu, X., et al., 2013. Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction. Nat. Commun. 4, 1515. Miller, B.A., et al., 2014. TRPM2 channels protect against cardiac ischemia-reperfusion injury. J. Biol. Chem. 289, 7615–7629. Miller, B.A., et al., 2013. The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 304, H1010–H1022. Ostapchenko, V.G., et al., 2015. The transient receptor potential melastatin 2 (TRPM2) channel contributes to β-amyloid oligomer-related neurotoxicity and memory impairment. J. Neurosci. 35, 15157–15169. Park, L., et al., 2014. The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction. Nat. Commun. 5, 5318. Perraud, A.L., et al., 2001. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411, 595–599. Pulido-Moran, M., et al., 2016. Curcumin and health. Molecules 2016 (21), 264. Shimizu, S., et al., 2014. Sensitization of H2O2-induced TRPM2 activation and
4. General conclusions and future perspectives Since TRPM2 is important for host defense responses to bacterial infections, its inhibition during infections may exacerbate symptoms. However, a number of studies using mouse disease models have suggested that TRPM2 contributes to the aggravation of various reactive oxygen species-related diseases. TRPM2 is attracting interest as a new target for suppressing various reactive oxygen species-related diseases; however, specific inhibitors are not yet available. In contrast, TRPA1 functions as a nociceptive receptor and O2 sensor. Therefore, direct TRPA1 channel blockers are considered to disrupt the physiological functions of TRPA1. We recently found that AG-related compounds blocked the H2O2-induced activation of TRPM2 and TRPA1 by scavenging the intracellular hydroxyl radical (Shimizu et al., 2014; Toda et al., 2016). Membrane-permeable hydroxyl radical scavengers represent one of the candidates to attenuate reactive oxygen species-related diseases through the blockage of TRPM2 and TRPA1. Curcumin ((1E,6E)-1,7-bis-(4-hy- droxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione), which is the main natural polyphenol in Curcuma longa (turmeric root), has been shown to exert strong inhibitory effects on H2O2-induced TRPM2 activation (Kheradpezhouh et al., 2016). On the other hand, curcumin activates and subsequently desensitizes TRPA1 (Leamy et al., 2011). Curcumin has been shown to exert beneficial effects on various diseases including inflammatory diseases (Pulido-Moran et al., 2016). The actions of curcumin described above have prompted us to speculate that TRPM2 inhibitors have clinically beneficial effects against reactive oxygen species-related diseases. 2
European Journal of Pharmacology xx (xxxx) xxxx–xxxx
S. Yamamoto, S. Shimizu subsequent interleukin-8 (CXCL8) production by intracellular Fe2+ in human monocytic U937 cells. Eur. J. Pharmacol. 742, 22–30. Shimizu, S., et al., 2015. Sensitization of H2O2-induced TRPM2 activation and subsequent interleukin-8 (CXCL8) production by intracellular Fe2+ in human monocytic U937 cells. Int. J. Biochem. Cell Biol. 68, 119–127. Shimizu, T., et al., 2013. Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury. J. Cereb. Blood Flow Metab. 33, 1549–1555. Story, G.M., et al., 2003. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829. Takahashi, N., et al., 2011. TRPA1 underlies a sensing mechanism for O2. Nat. Chem. Biol. 10, 701–711. Takahashi, N., et al., 2008. Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. Channels 2, 287–298.
Toda, T., et al., 2016. Inhibitory effects of Tyrphostin AG-related compounds on oxidative stress-sensitive transient receptor potential channel activation. Eur. J. Pharmacol. 786, 19–28. Yamamoto, S., et al., 2008. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat. Med. 14, 738–747. Yonezawa, R., et al., 2016. TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation. Free Radic. Biol. 90, 101–113. Yoshida, T., et al., 2006. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat. Chem. Biol. 2, 596–607. Zhong, Z., et al., 2013. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 4, 1611.
3
Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Significance of TRP channels in oxidative stress Shinichiro Yamamoto, Shunichi Shimizu
⁎
Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
A R T I C L E I N F O
A BS T RAC T
Keywords: TRP channels TRPM2 TRPA1 Reactive oxygen species Oxidative stress
Reactive oxygen species induce oxidative stress, leading to cell damage, but also function as signal transduction molecules. Transient receptor potential (TRP) channels have been attracting increasing attention as Ca2+permeable channels that sense environmental changes. The members of one class of TRP channels have emerged as reactive oxygen species sensors. The significance of Ca2+ signaling induced by the activation of reactive oxygen species-sensitive TRP channels under pathological conditions is currently being elucidated. The selective inhibition of reactive oxygen species-sensitive TRP channels represents a future challenge that may lead to new therapeutic strategies for the suppression of reactive oxygen species-related diseases.
1. Reactive oxygen species-sensitive TRP channels Transient receptor potential (TRP) channels have been divided into six subfamilies (C, V, M, P, ML, and A) (Clapham, 2003). TRPM2, TRPC5, TRPV1, and TRPA1 have been identified as reactive oxygen species-sensitive Ca2+-permeable channels. The activation of TRPM2 is triggered by ADP-ribose binding to the NudT9-H domain in its Cterminus (Perraud et al., 2001). We previously reported that the activation of TRPM2 is triggered by reactive oxygen species such as hydrogen peroxide (H2O2) (Hara et al., 2002). Reactive oxygen speciesinduced TRPM2 activation was also found to be triggered by the production of ADP-ribose in nuclei via poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase pathways (Fonfria et al., 2004) (Fig. 1). We recently demonstrated that H2O2-induced TRPM2 activation was mediated through the hydroxyl radical, which is produced by the reaction of H2O2 with intracellular Fe2+ (Fenton reaction) (Ishii et al., 2006; Shimizu et al., 2015). On the other hand, TRPC5, TRPV1, and TRPA1 are activated by reactive oxygen species through oxidative modifications to cysteine residues (Yoshida et al., 2006; Takahashi et al., 2008). The sensitivity of TRPA1 to reactive oxygen species is the greatest among the TRP channels. Cysteine residues on the poreforming region located within the plasma membrane and cytoplasmic N-terminal region are considered to be essential for the reactive oxygen species-induced activation of TRPC5/TRPV1 and TRPA1, respectively (Fig. 1). The activation of TRPA1 by H2O2 appears to be mediated by H2O2-derived hydroxyl radicals (Andersson et al., 2008) (Fig. 1). Since the hydroxyl radical is membrane impermeable, the activation of TRPV1 and TRPC5 may be triggered by H2O2 rather than the hydroxyl radical. The hydroxyl radical is more reactive than H2O2. TRPA1 rather
⁎
than TRPC5 and TRPV1 has been suggested to function as an oxidative stress sensor. Under pathological conditions such as inflammatory diseases and ischemia-reperfusion, various cells produce a large amount of reactive oxygen species (Dröge, 2002; Lambeth, 2004). Ca2+ influx via reactive oxygen species-sensitive TRP channels under pathological conditions has been shown to contribute to the aggravation of these diseases. 2. Pathological roles of TRPA1 Pungent compounds such as allyl isothiocyanate in mustard oil and noxious cold stimuli trigger the activation of TRPA1 (Story et al., 2003; Jordt et al., 2004), suggesting that TRPA1 functions as a nociceptive receptor. TRPA1 also functions as an O2 sensor, which plays an important role in maintaining O2 homeostasis (Takahashi et al., 2011). A previous study demonstrated that TRPA1 expressed in sensory neurons mediated neuropeptide release and chemokine production in the airways, and these are responsible for the aggravation of asthma (Caceres et al., 2009). Asthma is an inflammatory disease, and reactive oxygen species also function as mediators for the aggravation of symptoms (Henricks and Nijkamp, 2001). Therefore, TRPA1 is considered to be a sensor of oxidative stress and has been implicated in inflammatory diseases. 3. Pathological roles of TRPM2 Previous studies have indicated that the activation of TRPM2 in response to reactive oxygen species participates in the aggravation of inflammatory diseases. Ca2+ influxes through TRPM2 in monocytes/
Corresponding author. E-mail address: [email protected] (S. Shimizu).
http://dx.doi.org/10.1016/j.ejphar.2016.11.007 Received 22 August 2016; Received in revised form 20 October 2016; Accepted 2 November 2016 Available online xxxx 0014-2999/ © 2016 Elsevier B.V. All rights reserved.
Please cite this article as: Yamamoto, S., European Journal of Pharmacology (2016), http://dx.doi.org/10.1016/j.ejphar.2016.11.007
European Journal of Pharmacology xx (xxxx) xxxx–xxxx
S. Yamamoto, S. Shimizu
TRPM2
TRPA1
TRPV1 TRPC5 SH HS
NudT9-H
NudT9-H
HS
ADP-ribose NAD+ PARP PARG poly(ADP-ribose) neucleus
trans membrane
SH
OH fenton reaction
H2O2
PARG: poly(ADP-ribose) glycohydrolase PARP: poly(ADP-ribose) polymerase
Fig. 1. Differences in reactive oxygen species-induced activation mechanisms among reactive oxygen species-sensitive TRP channels.
References
macrophages and alveolar epithelial cells induce the production of cytokines and activation of NLRP3 inflammasomes, which contribute to the aggravation of inflammatory diseases (Yamamoto et al., 2008; Haraguchi et al., 2012; Zhong et al., 2013; Yonezawa et al., 2016). TRPM2 also plays important roles in host defense responses through innate immunoresponses such as monocyte activation and cytokine production (Knowles et al., 2011). Therefore, Trpm2 KO mice are more susceptible to bacterial infections. Reactive oxygen species production during ischemia-reperfusion also triggers the activation of TRPM2, which participates in brain, heart, and kidney ischemia-reperfusion injury (Hiroi et al., 2013; Shimizu et al., 2013; Gao et al., 2014; Gelderblom et al., 2014), whereas findings on heart ischemia-reperfusion injury have been controversial (Miller et al., 2013, 2014; Hoffman et al., 2015). Additionally, TRPM2 has been shown to contribute to the development of acetaminophen-induced liver injury, radiation-induced tissue damage, and Alzheimer's disease, in which oxidative stress is accelerated (Liu et al., 2013; Kheradpezhouh et al., 2014; Park et al., 2014; Ostapchenko et al., 2015).
Andersson, D.A., et al., 2008. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J. Neurosci. 28, 2485–2494. Caceresa, A.I., et al., 2009. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Natl. Acad. Sci. USA 106, 9099–9104. Clapham, D.E., 2003. TRP channels as cellular sensors. Nature 426, 517–524. Dröge, W., 2002. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95. Fonfria, E., et al., 2004. TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br. J. Pharmacol. 143, 186–192. Gao, G., et al., 2014. TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1. J. Clin. Invest. 124, 4989–5001. Gelderblom, M., et al., 2014. Transient receptor potential melastatin subfamily member 2 cation channel regulates detrimental immune cell invasion in ischemic stroke. Stroke 45, 3395–3402. Hara, Y., et al., 2002. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol. Cell 9, 163–173. Haraguchi, K., et al., 2012. TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice. J. Neurosci. 32, 3931–3941. Henricks, P.A., Nijkamp, F.P., 2001. Reactive oxygen species as mediators in asthma. Pulm. Pharmacol. Ther. 14, 409–420. Hiroi, T., et al., 2013. Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischemia/reperfusion injury. Cardiovasc. Res. 97, 271–281. Hoffman, N.E., et al., 2015. Ca2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am. J. Physiol. Heart Circ. Physiol. 308, H637–H650. Ishii, M., et al., 2006. Intracellular-produced hydroxyl radical mediates H2O2-induced Ca2+ influx and cell death in rat beta-cell line RIN-5F. Cell Calcium 39, 487–494. Jordt, S.E., et al., 2004. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265. Kheradpezhouh, E., Barritt, G.J., Rychkov, G.Y., 2016. Cumin inhibits activation of TRPM2 channels in rat hepatocytes. Redox Biol. 7, 1–7. Kheradpezhouh, E., et al., 2014. TRPM2 channels mediate acetaminophen-induced liver damage. Proc. Natl. Acad. Sci. USA 111, 3176–3181. Knowles, H., et al., 2011. Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. Proc. Natl. Acad. Sci. USA 108, 11578–11583. Lambeth, J.D., 2004. NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189. Leamy, A.W., et al., 2011. Curcumin ((E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-3,5-dione) activates and desensitizes the nociceptor ion channel TRPA1. Neurosci. Lett. 503, 157–162. Liu, X., et al., 2013. Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction. Nat. Commun. 4, 1515. Miller, B.A., et al., 2014. TRPM2 channels protect against cardiac ischemia-reperfusion injury. J. Biol. Chem. 289, 7615–7629. Miller, B.A., et al., 2013. The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 304, H1010–H1022. Ostapchenko, V.G., et al., 2015. The transient receptor potential melastatin 2 (TRPM2) channel contributes to β-amyloid oligomer-related neurotoxicity and memory impairment. J. Neurosci. 35, 15157–15169. Park, L., et al., 2014. The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction. Nat. Commun. 5, 5318. Perraud, A.L., et al., 2001. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411, 595–599. Pulido-Moran, M., et al., 2016. Curcumin and health. Molecules 2016 (21), 264. Shimizu, S., et al., 2014. Sensitization of H2O2-induced TRPM2 activation and
4. General conclusions and future perspectives Since TRPM2 is important for host defense responses to bacterial infections, its inhibition during infections may exacerbate symptoms. However, a number of studies using mouse disease models have suggested that TRPM2 contributes to the aggravation of various reactive oxygen species-related diseases. TRPM2 is attracting interest as a new target for suppressing various reactive oxygen species-related diseases; however, specific inhibitors are not yet available. In contrast, TRPA1 functions as a nociceptive receptor and O2 sensor. Therefore, direct TRPA1 channel blockers are considered to disrupt the physiological functions of TRPA1. We recently found that AG-related compounds blocked the H2O2-induced activation of TRPM2 and TRPA1 by scavenging the intracellular hydroxyl radical (Shimizu et al., 2014; Toda et al., 2016). Membrane-permeable hydroxyl radical scavengers represent one of the candidates to attenuate reactive oxygen species-related diseases through the blockage of TRPM2 and TRPA1. Curcumin ((1E,6E)-1,7-bis-(4-hy- droxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione), which is the main natural polyphenol in Curcuma longa (turmeric root), has been shown to exert strong inhibitory effects on H2O2-induced TRPM2 activation (Kheradpezhouh et al., 2016). On the other hand, curcumin activates and subsequently desensitizes TRPA1 (Leamy et al., 2011). Curcumin has been shown to exert beneficial effects on various diseases including inflammatory diseases (Pulido-Moran et al., 2016). The actions of curcumin described above have prompted us to speculate that TRPM2 inhibitors have clinically beneficial effects against reactive oxygen species-related diseases. 2
European Journal of Pharmacology xx (xxxx) xxxx–xxxx
S. Yamamoto, S. Shimizu subsequent interleukin-8 (CXCL8) production by intracellular Fe2+ in human monocytic U937 cells. Eur. J. Pharmacol. 742, 22–30. Shimizu, S., et al., 2015. Sensitization of H2O2-induced TRPM2 activation and subsequent interleukin-8 (CXCL8) production by intracellular Fe2+ in human monocytic U937 cells. Int. J. Biochem. Cell Biol. 68, 119–127. Shimizu, T., et al., 2013. Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury. J. Cereb. Blood Flow Metab. 33, 1549–1555. Story, G.M., et al., 2003. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829. Takahashi, N., et al., 2011. TRPA1 underlies a sensing mechanism for O2. Nat. Chem. Biol. 10, 701–711. Takahashi, N., et al., 2008. Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. Channels 2, 287–298.
Toda, T., et al., 2016. Inhibitory effects of Tyrphostin AG-related compounds on oxidative stress-sensitive transient receptor potential channel activation. Eur. J. Pharmacol. 786, 19–28. Yamamoto, S., et al., 2008. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat. Med. 14, 738–747. Yonezawa, R., et al., 2016. TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation. Free Radic. Biol. 90, 101–113. Yoshida, T., et al., 2006. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat. Chem. Biol. 2, 596–607. Zhong, Z., et al., 2013. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 4, 1611.
3