Aminoethoxydiphenyl Borate and Flufenamic Acid Inhibit Ca2+ Influx Through TRPM2 Channels in Rat Dorsal Root Ganglion Neurons Activated by ADP-Ribose and Rotenone (original) (raw)
Abstract
Exposure to oxidative stress causes health problems, including sensory neuron neuropathy and pain. Rotenone is a toxin used to generate intracellular oxidative stress in neurons. However, the mechanism of toxicity in dorsal root ganglion (DRG) neurons has not been characterized. Melastatin-like transient receptor potential 2 (TRPM2) channel activation and inhibition in response to oxidative stress, ADP-ribose (ADPR), flufenamic acid (FFA) and 2-aminoethoxydiphenyl borate (2-APB) in DRG neurons are also not clear. We tested the effects of FFA and 2-APB on ADPR and rotenone-induced TRPM2 cation channel activation in DRG neurons of rats. DRG neurons were freshly isolated from rats and studied with the conventional whole-cell patch-clamp technique. Rotenone, FFA and 2-APB were extracellularly added through the patch chamber, and ADPR was applied intracellularly through the patch pipette. TRPM2 cation currents were consistently induced by ADPR and rotenone. Current densities of the neurons were higher in the ADPR and rotenone groups than in control. The time courses (gating times) in the neurons were longer in the rotenone than in the ADPR group. ADPR and rotenone-induced TRPM2 currents were totally blocked by 2-APB and partially blocked by FFA. In conclusion, TRPM2 channels were constitutively activated by ADPR and rotenone, and 2-APB and FFA induced an inhibitory effect on TRPM2 cation channel currents in rat DRG neurons. Since oxidative stress is a common feature of neuropathic pain and diseases of sensory neurons, the present findings have broad application to the etiology of neuropathic pain and diseases of DRG neurons.
Access this article
Subscribe and save
- Get 10 units per month
- Download Article/Chapter or eBook
- 1 Unit = 1 Article or 1 Chapter
- Cancel anytime Subscribe now
Buy Now
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Instant access to the full article PDF.
Similar content being viewed by others
References
- Bao L, Avshalumov MV, Rice ME (2005) Partial mitochondrial inhibition causes striatal dopamine release suppression and medium spiny neuron depolarization via H2O2 elevation, not ATP depletion. J Neurosci 26:10029–10040
Article Google Scholar - Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306
Article PubMed CAS Google Scholar - Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494
Article PubMed Google Scholar - Buelow B, Song Y, Scharenberg AM (2008) The poly(ADP-ribose) polymerase PARP-1 is required for oxidative stress-induced TRPM2 activation in lymphocytes. J Biol Chem 283:24571–24583
Article PubMed CAS Google Scholar - Clapham DE (2007) SnapShot: mammalian TRP channels. Cell 129:220
Article PubMed Google Scholar - Cormier A, Morin C, Zini R, Tillement JP, Lagrue G (2003) Nicotine protects rat brain mitochondria against experimental injuries. Neuropharmacology 44:642–652
Article PubMed CAS Google Scholar - Freestone PS, Chung KK, Guatteo E, Mercuri NB, Nicholson LF, Lipski J (2009) Acute action of rotenone on nigral dopaminergic neurons—involvement of reactive oxygen species and disruption of Ca2+ homeostasis. Eur J Neurosci 30:1849–1859
Article PubMed Google Scholar - Guse AH (2005) Second messenger function and the structure–activity relationship of cyclic adenosine diphosphoribose (cADPR). FEBS J 272:4590–4597
Article PubMed CAS Google Scholar - Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T et al (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9:163–173
Article PubMed CAS Google Scholar - Hill K, Benham CD, McNulty S, Randall AD (2004) Flufenamic acid is a pH-dependent antagonist of TRPM2 channels. Neuropharmacology 47:450–460
Article PubMed CAS Google Scholar - Ishii M, Shimizu S, Hara Y, Hagiwara T, Miyazaki A, Mori Y, Kiuchi Y (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
Article PubMed CAS Google Scholar - Kühn FJ, Kühn C, Naziroglu M, Lückhoff A (2009) Role of an N-terminal splice segment in the activation of the cation channel TRPM2 by ADP-ribose and hydrogen peroxide. Neurochem Res 34:227–233
Article PubMed Google Scholar - Nazıroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001
Article PubMed Google Scholar - Nazıroğlu M (2011) TRPM2 cation channels, oxidative stress and neurological diseases: where are we now? Neurochem Res 36:355–366
Article PubMed Google Scholar - Nazıroğlu M, Lückhoff A (2008a) Effects of antioxidants on calcium influx through TRPM2 channels in transfected cells activated by hydrogen peroxide. J Neurol Sci 270:152–158
Article PubMed Google Scholar - Nazıroğlu M, Lückhoff A (2008b) A calcium influx pathway regulated separately by oxidative stress and ADP-ribose in TRPM2 channels: single channel events. Neurochem Res 33:1256–1262
Article PubMed Google Scholar - Nazıroğlu M, Lückhoff A, Jüngling E (2007) Antagonist effect of flufenamic acid on TRPM2 cation channels activated by hydrogen peroxide. Cell Biochem Funct 25:383–387
Article PubMed Google Scholar - Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM (2001) ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595–599
Article PubMed CAS Google Scholar - Perraud AL, Takanishi CL, Shen B, Kang S, Smith MK, Schmitz C, Knowles HM, Ferraris D, Li W, Zhang J, Stoddard BL, Scharenberg AM (2005) Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J Biol Chem 280:6138–6148
Article PubMed CAS Google Scholar - Salazar M, Pariente JA, Salido GM, González A (2008) Ebselen increases cytosolic free Ca2+ concentration, stimulates glutamate release and increases GFAP content in rat hippocampal astrocytes. Toxicology 244:280–291
Article PubMed CAS Google Scholar - Staaf S, Franck MC, Marmigère F, Mattsson JP, Ernfors P (2010) Dynamic expression of the TRPM subgroup of ion channels in developing mouse sensory neurons. Gene Expr Patterns 10:65–74
Article PubMed CAS Google Scholar - Togashi K, Inada H, Tominaga M (2008) Inhibition of the transient receptor potential cation channel TRPM2 by 2-aminoethoxydiphenyl borate (2-APB). Br J Pharmacol 153:1324–1330
Article PubMed CAS Google Scholar - Wehage E, Eisfeld J, Heiner I, Jüngling E, Zitt C, Lückhoff A (2002) Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem 277:23150–23156
Article PubMed CAS Google Scholar - Xu SZ, Zeng F, Boulay G, Grimm C, Harteneck C, Beech DJ (2005) Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol 145:405–414
Article PubMed CAS Google Scholar
Acknowledgements
There was no financial support for the study. Mustafa Nazıroğlu formulated the present hypothesis and was responsible for writing the report. Bilal Çiğ isolated the DRG neurons from rats. Cemil Özgül and Ömer Çelik were responsible for patch-clamp experiment. Ercan Sözbir was responsible for preparation of figures. An abstract of the study will be submitted to the 10th National Neuroscience Congress in Istanbul, Turkey, April 8–12, 2011.
Conflict of interest
None.
Author information
Authors and Affiliations
- Department of Biophysics, Faculty of Medicine, University of Suleyman Demirel, 32260, Isparta, Turkey
Mustafa Nazıroğlu, Cemil Özgül, Ömer Çelik, Bilal Çiğ & Ercan Sözbir
Authors
- Mustafa Nazıroğlu
You can also search for this author inPubMed Google Scholar - Cemil Özgül
You can also search for this author inPubMed Google Scholar - Ömer Çelik
You can also search for this author inPubMed Google Scholar - Bilal Çiğ
You can also search for this author inPubMed Google Scholar - Ercan Sözbir
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toMustafa Nazıroğlu.
Rights and permissions
About this article
Cite this article
Nazıroğlu, M., Özgül, C., Çelik, Ö. et al. Aminoethoxydiphenyl Borate and Flufenamic Acid Inhibit Ca2+ Influx Through TRPM2 Channels in Rat Dorsal Root Ganglion Neurons Activated by ADP-Ribose and Rotenone.J Membrane Biol 241, 69–75 (2011). https://doi.org/10.1007/s00232-011-9363-9
- Received: 13 March 2011
- Accepted: 21 March 2011
- Published: 21 April 2011
- Issue Date: May 2011
- DOI: https://doi.org/10.1007/s00232-011-9363-9