Skip to main content

Advertisement

Springer Nature Link
Log in

Sensitization of vanilloid receptor involves an increase in the phosphorylated form of the channel

  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

A vanilloid receptor (VR1, now known as TRPV1) is an ion channel activated by vanilloids, including capsaicin (CAP) and resiniferatoxin (RTX), which are pungent ingredients of plants. Putative endogenous activators (anandamide and metabolites of arachidonic acid) are weak activators of VR1 compared to capsaicin and RTX, and the concentrations of the physiological condition of those activators are not sufficient to induce significant activation of VR1. One way to overcome the weak activation of endogenous activators would be the sensitization of VR1, with the phosphorylation of the channel being one possibility. The phosphorylation of VR1 by several kinases has been reported, mostly by indirect evidence. Here, using an in vivo phosphorylation method, the VR1 channel was shown to be sensitized by phosphorylation of the channel itself by multiple pathways involving PKA, PKC and acid. Also, in sensitizing VR1, BK appeared to show activation of PKC for the sensitization of VR1 by phosphorylation of the channel.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  • Amos, S., Martin, P. M., Polar, G. A., Parsons, S. J., and Hussaini, I. M., Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivationvia protein kinase C{delta}/c-Src pathways in glioblastoma cells.J. Biol. Chem., 280, 7729–7738 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., and Julius, D., The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature, 389, 816–824 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., Koltzenburg, M., Basbaum, A. I., and and Julius, D., Impaired nociception and pain sensation in mice lacking the capsaicin receptor.Science, 288, 306–313 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Cesare, P., Moriondo, A., Vellani, V., and McNaughton, P. A., Ion channels gated by heat.Proc. Natl. Acad. Sci. U.S.A., 96, 7658–63 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Cesare, P. and McNaughton, P., A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin.Proc. Natl. Acad. Scl. U.S.A., 93, 15435–15439 (1996).

    Article  CAS  Google Scholar 

  • Cheng, S. H., Rich, D. P., Marshall, J., Gregory, R. J., Welsh, M. J., and Smith, A. E., Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel.Cell, 66, 1027–1036 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Chuang, H. H., Prescott, E. D., Kong, H., Shields, S., Jordt, S. E., Basbaum, A. I., Chao, M. V., and Julius, D., Bradykinin and nerve growth factor release the capsaicin receptor from Ptdlns(4,5) P2-mediated inhibition.Nature, 411, 957–962 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Cortright, D. N. and Szallasi, A., Biochemical pharmacology of the vanilloid receptor TRPV1.An update. Eur. J. Biochem., 271, 1814–1819 (2004).

    Article  CAS  Google Scholar 

  • Davies, S. P., Reddy, H., Caivano, M., and Cohen, P., Specificity and mechanism of action of some commonly used protein kinase inhibitors.Biochem. J., 351 (part 1), 95–105 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Davis, J. B., Gray, J., Gunthorpe, M. J., Hatcher, J. P., Davey, P. T., Overend, P., Harries, M. H., Latcham, J., Clapham, C., Atkinson, K., Hughes, S. A., Rance, K., Grau, E., Harper, A. J., Pugh, P. L., Rogers, D. C., Bingham, S., Randall, A., and Sheardown, S. A., Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.Nature, 405, 183–187 (2000).

    Article  PubMed  CAS  Google Scholar 

  • De Petrocellis, L., Harrison, S., Bisogno, T., Tognetto, M., Brandi, I., Smith, G. D., Creminon, C., Davis, J. B., Geppetti, P., and Di Marzo, V. J., The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase.Neurochem., 77, 1660–1663 (2001).

    Article  Google Scholar 

  • Di Marzo, V., Bisogno, T., and De Petrocellis, L., Anandamide: some like it hot.Trends Pharmacol. Sci., 22, 346–349 (2001).

    Article  PubMed  Google Scholar 

  • Docherty, R. J., Yeats, J. C., and Piper, A. S., Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats.Br. J. Pharmacol., 121, 1461–1467 (1996).

    Article  Google Scholar 

  • Hong, S. and Wiley, J. W., Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1.J. Biol. Chem., 280, 618–627 (2004).

    PubMed  Google Scholar 

  • Huang, S. M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T. J., Krey, J. F., Chu, C. J., Miller, J. D., Davies, S. N., Geppetti, P., Walker, J. M., and Di Marzo, V., An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors.Proc. Natl. Acad. Sci. U.S.A., 99, 8400–8405 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Hwang, S. W., Cho, H., Kwak, J., Lee, S. Y., Kang, C. J., Jung, J., Cho, S., Min, K. H., Suh, Y. G., Kim, D., and Oh, U., Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances.Proc. Natl. Acad. Sci. U. S. A., 97, 6155–6160 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Jung, J., Shin, J. S., Lee, S. Y., Hwang, S. W., Koo, J., Cho, H., and Oh, U., Phosphorylation of vanilloid receptor 1 by Ca2+/ calmodulin-dependent kinase II regulates its vanilloid binding.J. Biol. Chem., 279, 7048–7054 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Khasar, S. G., Lin, Y. H., Martin, A., Dadgar, J., McMahon, T., Wang, D., Hundle, B., Aley, K. O., Isenberg, W., McCarter, G., Green, P. G., Hodge, C. W., Levine, J. D., and Messing, R. O., A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice.Neuron, 24, 253–260 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Lazar, J., Szabo, T., Marincsak, R., Kovacs, L., Blumberg, P. M., and Biro, T., Sensitization of recombinant vanilloid receptor-1 by various neurotrophic factors.Life Sci., 75, 153–163 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Nakamura, J., Suda, T., Ogawa, Y., Takeo, T., Suga, S., and Wakui, M., Protein Kinase C-dependent and — independent inhibition of Ca2+ influx by phorbol ester in rat pancreatic β-cells.Cell Signal, 13, 199–205 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Numazaki, M., Tominaga, T., Toyooka, H., and Tominaga, M., Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues.J. Biol. Chem., 277, 13375–13382 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Oh, U., Hwang, S. W., and Kim, D., Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons.J. Neurosci., 16, 1659–1667 (1996).

    PubMed  CAS  Google Scholar 

  • Olah, Z., Karai, L., and Iadarola, M. J., Protein kinase C alpha is required for vanilloid receptor 1 activation. Evidence for multiple signaling pathways.J. Biol. Chem., 277, 35752–35759 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Olah, Z., Karai, L., and Iadarola, M. J., Anandamide activates vanilloid receptor 1 (VR1) at acidic pH in dorsal root ganglia neurons and cells ectopically expressing VR1.J. Biol. Chem., 276, 31163–31170 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Premkumar, L. S. Interaction between vanilloid receptors and purinergic metabotropic receptors: pain perception and beyond.Proc. Natl. Acad. Sci. U.S.A., 98, 6537–6539 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Premkumar, L. S. and Ahern, G. P., Induction of vanilloid receptor channel activity by protein kinase C.Nature, 408, 985–990 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Rathee, P. K., Distler, C., Obreja, O., Neuhuber, W., Wang, G. K., Wang, S. Y., Nau, C., and Kress, M., PKA/AKAPA/R-1 module: A common link of Gs-mediated signaling to thermal hyperalgesia.J. Neurosci., 22, 4740–4745 (2002).

    PubMed  CAS  Google Scholar 

  • Roberts, N. A., Marber, M. S., and Avkiran, M., Specificity of action of bisindolylmaleimide protein kinase C inhibitors: do they inhibit the 70 kDa ribosomal S6 kinase in cardiac myocytes?Biochem. Pharmacol., 68, 1923–1928 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Samuvel, D. J., Jayanthi, L. D., Bhat, N. R., and Ramamoorthy, S., A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression.J. Neurosci., 25, 29–41 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Shin, J., Cho, H., Hwang, S. W., Jung, J., Shin, C. Y., Lee, S. Y., Kim, S. H., Lee, M. G., Choi, Y. H., Kim, J., Haber, N. A., Reichling, D. B., Khasar, S., Levine, J. D., and Oh, U., Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia.Proc. Natl. Acad. Sci. U.S.A., 99, 10150–10155 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Smart, D., Gunthorpe, M. J., Jerman, J. C., Nasir, S., Gray, J., Muir, A. I., Chambers, J. K., Randall, A. D., and Davis, J. B., The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1).Br. J. Pharmacol., 129, 227–230 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Smith, J. A., Davis, C. L., and Burgess, G. M., Prostaglandin E2-induced sensitization of bradykinin-evoked responses in rat dorsal root ganglion neurons is mediated by cAMP-dependent protein kinase A.Eur. J. Neurosci., 12, 3250–3258 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Szolcsanyi, J., Anandamide and the question of its functional role for activation of capsaicin receptors.Trends. Pharmacol. Sci., 21, 203–204 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Toullec, D., Pianetti, P., Coste, H., Bellevergue, P., Grand-Perret, T., Ajakane, M., Baudet, V., Boissin, P., Boursier, E., and Loriolle, F., The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.J. Biol. Chem., 266, 15771–15781 (1991).

    PubMed  CAS  Google Scholar 

  • Vellani, V., Mapplebeck, S., Moriondo, A., Davis, J. B., and McNaughton, P. A., Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide.J. Physiol., 534, 813–825 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Wang, Y., Kedei, N., Wang, M., Wang, Q. J., Huppler, A., Toth, A., Tran, R., and Blumberg, P. M., Interaction between PKCmu and the vanilloid receptor type 1.J. Biol. Chem., 279, 53674–53682 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Welch, J. M., Simon, S. A., and Reinhart, P. H., The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat.Proc. Natl. Acad. Sci. U.S.A., 97, 13889–13894 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Xu, F., Satoh, E., and Iijima, T., Protein kinase C-mediated Ca2+ entry in HEK 293 cells transiently expressing human TRPV4.Br. J. Pharmacol., 140, 413–21 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Zygmunt, P. M., Andersson, D. A., and Hogestatt, E. D., Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nervesvia a CB1 and CB2 cannabinoid receptor-independent mechanism.J. Neurosci., 22, 4720–4727 (2002).

    PubMed  CAS  Google Scholar 

  • Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H., Sorgard, M., Di Marzo, V., Julius, D., and Hogestatt, E. D., Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide.Nature, 400, 452–457 (1999).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Food and Nutrition, Seoil College, 131-702, Seoul

    Jae-Hag Lee

  2. Department of Horticulture, Hankyong National University, 456-749, Gyonggi, Korea

    Kwon Kyoo Kang

  3. Graduate School of Bio & Information Technology, Hankyong National University, 456-749, Gyonggi, Korea

    Sue-Yun Hwang & Kang Duk Choi

  4. The Sensory Research Center, National Creative Research Initiatives, College of Pharmacy, Seoul National University, 151-742, Seoul, Korea

    Uhtaek Oh

  5. Department of Genomic Engineering, Genetic Informatics Center, GRRC, Hankyong National University, 67 Sukjong-dong, Ansung-city, 456-749, Gyonggi, Korea

    Soon-Youl Lee, Jae-Hag Lee, Kwon Kyoo Kang, Sue-Yun Hwang, Kang Duk Choi & Uhtaek Oh

Authors
  1. Soon-Youl Lee
    View author publications

    Search author on:PubMed Google Scholar

  2. Jae-Hag Lee
    View author publications

    Search author on:PubMed Google Scholar

  3. Kwon Kyoo Kang
    View author publications

    Search author on:PubMed Google Scholar

  4. Sue-Yun Hwang
    View author publications

    Search author on:PubMed Google Scholar

  5. Kang Duk Choi
    View author publications

    Search author on:PubMed Google Scholar

  6. Uhtaek Oh
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Soon-Youl Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, SY., Lee, JH., Kang, K.K. et al. Sensitization of vanilloid receptor involves an increase in the phosphorylated form of the channel. Arch Pharm Res 28, 405–412 (2005). https://doi.org/10.1007/BF02977669

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02977669

Key words