• 1990 (Vol.4)
  • 1989 (Vol.3)
  • 1988 (Vol.2)
  • 1987 (Vol.1)

Involvement of protein kinase C in receptor-mediated signaling processes

© 2019 V. A. Penniyaynen, V. B. Plakhova, I. V. Rogachevsky, S. G. Terekhin, S. A. Podzorova, B. V. Krylov

Pavlov Institute of Physiology of Russian Academy of Sciences, 199034 St. Petersburg, Makarova emb., 6, Russia

Received 19 Feb 2019

Comenic acid is a specific agonist of opioid-like receptors found in the sensory neuron membrane. These receptors are coupled to NaV1.8 channels responsible for nociceptive information coding. Patch-clamp data show that at the membrane level, the ligand-receptor binding of comenic acid is manifested in a decrease in the effective charge transfer of NaV1.8 channels activation gating device. The use of a specific protein kinase C inhibitor (Tamoxifen) did not affect this receptor-activated mechanism. A completely different result is obtained at the tissue level: Tamoxifen totally blocks the signal triggered by comenic acid and directed radially to the nerve cell genome. Elimination of the neurite- stimulating effect of comenic acid by Tamoxifen demonstrates that protein kinase C participates in intracellular cascade processes under study as a sequential unit.

Key words: comenic acid, nociception, sensory neurons, patch-clamp method, organotypic nerve tissue culture method, NaV1.8 channels, protein kinase C

DOI: 10.1134/S0235009219030089

Cite: Penniyaynen V. A., Plakhova V. B., Rogachevsky I. V., Terekhin S. G., Podzorova S. A., Krylov B. V. Uchastie proteinkinazy s v retseptor-oposredovannykh signalnykh protsessakh [Involvement of protein kinase c in receptor-mediated signaling processes]. Sensornye sistemy [Sensory systems]. 2019. V. 33(3). P. 204-211 (in Russian). doi: 10.1134/S0235009219030089


  • Krylov B., Derbenev A., Podzorova S., Lyudyno M., Kuz’min A., Izvarina N. Morphine decreases the voltage sensitivity of slow sodium channels. Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova. 1999. V. 85 (2). Р. 225–236. (in Russian)
  • Penniyaynen V.A., Kipenko A.V., Lopatina E.V., Krylov B.V. Involvement of р38 МАРК of sensory neurons in ouabain-activated signaling cascade. Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova. 2016. V.102(12). P. 1472–1478. (in Russian).
  • Penniyaynen V.A., Yachnev I.L., Kipenko A.V., Lopatina E.V., Krylov, B.V. Probable role of Src-kinase in reception of infrared irradiation. Sensornye Sistemy. [Sensory systems]. 2014. V. 28. P. 90–94. (in Russian).
  • Plakhova V.B., Podzorova S.A., Mishchenko I.V., Bagraev N.T., Klyachkin, L.E., Malyarenko A.M., Romanov V.V., Krylov B.V. Probable effects of infrared irradiation on sensory neuron membrane. Sensorniye Sistemy. [Sensory systems]. 2003. V. 17 (1). Р. 24–31. (in Russian).
  • Shelykh T.N., Rogachevskii I.V., Moshkina V.N., Podzorova S.A., Krylov, B.V., Plakhova V.B. Investigation of the effect of PP2 Src kinase inhibitor on the ability of ouabain to modulate slow sodium channels. Sensornye Sistemy. [Sensory systems]. 2017. V. 31 (1). P. 16–21. (in Russian).
  • Almers W. Gating currents and charge movements in excitable membranes. Rev. Physiol. Biochem. Pharmacol. 1978. V. 82. № 7. P. 97–190.
  • Aperia A., Akkuratov E.E., Fontana X.J., Brismar H. Na+K+-ATPase, a new class of plasma membrane receptors. Am. J. Physiol. Cell Physiol. 2016. V. 310. P. C491– C495.
  • Cui X., Xie Z. Protein interaction and Na/K-ATPase-mediated signal transduction. Molecules. 2017. V. 22. № 6. E990.
  • Elliott A.A., Elliott J.R. Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia. J. Physiol. (Lond.). 1993. V. 463. № 4. P. 39–56.
  • Hamill O.P., Marty A., Neher E., Sakmann B., Sigworth F. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers. Arch. 1981. V. 391. № 1. P. 85–100.
  • Hamlyn J.M., Blaustein M.P., Bova S., DuCharme D.W., Harris D.W., Mandel F., Mathews W.R., Ludens J.H. Identification and characterization of a ouabain-like compound from human plasma. Proc. Natl. Acad. Sci. USA. 1991. V. 88. № 21. P. 6259–6263.
  • Hodgkin A.L., Huxley A.F. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J. Physiol. 1952. V. 116. № 4. P. 449–472.
  • Khalaf F.K., Dube P., Mohamed A., Tian J., Malhotra D., Haller S.T., Kennedy D.J. Cardiotonic steroids and the sodium trade balance: new insights into trade-off mechanisms mediated by the Na+/K+-ATPase. Int. J. Mol. Sci. 2018. V. 19 № 92576. https://doi.org/10.3390/ijms19092576
  • Kometiani P., Li J., Gnudi L., Kahn B.B., Askari A., Xie Z. Multiple signal transduction pathways link Na+/K+ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. J. Biol. Chem. 1998. V. 273. № 24. P. 15249–15256.
  • Kostyuk P.G., Krishtal O.A., Pidoplichko V.I. Effect of internal fluoride and phosphate on membrane currents during intracellular dialysis of nerve cells. Nature. 1975. V. 257. № 5528. P. 691–693.
  • Krylov B.V., Rogachevskii I.V., Shelykh T.N., Plakhova V.B. Frontiers in pain science. Volume 1. New nonopioid analgesics: understanding molecular mechanisms on the basis of patch-clamp and quantumchemical studies. Sharjah, U.A.E., Bentham Science Publishers Ltd., 2017. 203 p. https://doi.org/10.2174/97816080593001170101
  • Liu L., Zhao X., Pierre S.V., Askari A. Association of PI3KAkt signaling pathway with digitalis-induced hypertrophy of cardiac myocytes. Am. J. Physiol. 2007. V. 293. № 5. P. C1489–C1497. https://doi.org/10.1152/ajpcell.00158.2007
  • Madan N., Xu Y., Duan Q., Banerjee M., Larre I., Pierre S.V., Xie Z. Src-independent ERK signaling through the rat α3 isoform of Na/K-ATPase. Am. J. Physiol. Cell Physiol. 2017. V. 312. № 3. C222–C232. https://doi.org/10.1152/ajpcell.00199.2016
  • Penniyaynen V., Plakhova V., Rogachevskii I., Krylov B. Src kinase is involved in comenic acid-triggered signaling pathways in sensory neurons. Activitas nervosa superior rediviva. 2018. V. 60. № 1. P. 19–27.
  • Plakhova V., Rogachevsky I., Lopatina E., Shelykh T., Butkevich I., Mikhailenko V., Otellin V., Podzorova S., Krylov B. A novel mechanism of modulation of slow sodium channels: from ligand-receptor interaction to design of an analgesic medicine. Activitas nervosa superior rediviva. 2014. V. 56. № 3–4. P. 55–64.
  • Pratt R.D., Brickman C.R., Cottrill C.L., Shapiro J.I., Liu J. The Na/K-ATPase signaling: from specific ligands to general reactive oxygen species. Int. J. Mol. Sci. 2018. 19. № 9. 2600. https://doi.org/10.3390/ijms19092600
  • Tian J., Cai T., Yuan Z., Wang H., Liu L., Haas M., Maksimova E., Huang X.Y., Xie Z.J. Binding of Src to Na+/K+-ATPase forms a functional signaling complex. Mol. Biol. Cell. 2006. V. 17. № 1. P. 317–326. https://doi.org/10.1091/mbc.e05-08-0735
  • Tsubaki M., Takeda T., Matsumoto M., Kato N., Yasuhara S., Koumoto Y.I., Imano M., Satou T., Nishida S. Tamoxifen suppresses paclitaxel-, vincristine-, and bortezomib-induced neuropathy via inhibition of the protein kinase C/extracellular signal-regulated kinase pathway. Tumour Biol. 2018. V. 40. № 10. P. 1–13. https://doi.org/10.1177/1010428318808670
  • Valvassori S.S., Dal-Pont G.C., Resende W.R., Varela R.B., Peterle B.R., Gava F.F., Mina F.G., Cararo J.H., Carvalho A.F., Quevedo J. Lithium and tamoxifen modulate behavior and protein kinase c activity in the animal model of mania induced by ouabain. Int. J. Neuropsychopharmacol. 2017. V. 20. № 11. P. 877–885. https://doi.org/10.1093/ijnp/pyx049
  • Wu J., Akkuratov E.E, Bai Y., Gaskill C.M., Askari A., Liu L. Cell signaling associated with Na(+)/K(+)-ATPase: activation of phosphatidylinositide 3-kinase IA/Akt by ouabain is independent of Src. Biochemistry. 2013. V. 52. № 50. P. 9059–9067. https://doi.org/10.1021/bi4011804
  • Xie Z., Askari A. Na(+)/K(+)-ATPase as a signal transducer. Eur. J. Biochem. 2002. V. 269. № 10. P. 2434–2439. https://doi.org/10.1046/j.1432-1033.2002.02910.x