Cyclic polypeptide PP-14 modulates the voltage sensitivity of slow sodium channels

© 2016 V. B. Plakhova, I. V. Rogachevsky, Т. N. Shelykh, S. A. Podzorova, B. V. Krylov

Pavlov Institute of Physiology, Russian Academy of Sciences Saint-Petersburg, 199034 Makarova emb., 6

Received 04 Apr 2016

An ability of polypeptide PP-14 to modulate the excitability of nociceptive neuron membrane was investigated by patch- clamp method. The agent was demonstrated to decrease the voltage sensitivity of slow sodium channels NaV1.8, responsible for nociceptive signal coding. Extracellular application of PP-14 induced a significant decrease in the effective charge transfer (Zeff) of the activation gating machinery of NaV1.8 channels, which indicates that the polypeptide may produce analgesia. Nevertheless, the effect of PP-14 is less pronounced as compared to a sharp decrease in nociceptive neuron excitability induced by a more complex molecule of defensin NP-1 applied at subnanomolar concentrations. Quantum- chemical analysis of PP-14 and NP-1 steric structures made it possible to account for the relative efficacy of ligand- receptor binding of these polypeptides.

Key words: nociception, patch-clamp method, slow sodium channels, polypeptides, quantum-chemical calculations

Cite: Plakhova V. B., Rogachevsky I. V., Shelykh Т. N., Podzorova S. A., Krylov B. V.. Tsiklicheskii polipeptid pp-14 moduliruet potentsialochuvstvitelnost medlennykh natrievykh kanalov [Cyclic polypeptide pp-14 modulates the voltage sensitivity of slow sodium channels]. Sensornye sistemy [Sensory systems]. 2016. V. 30(3). P. 234-240 (in Russian).


  • Mozhaeva G.N., Naumov A.P., Nosyreva E.D. Kinetics of sodium current decay during normal axon membrane repolarization and in the presence of scorpion toxin // Neirofiziologiia. 1980. V. 12(5). P. 541–549 [In Russian].
  • Nozdrachev A.D., Krylov B.V., Sabanov V.S., Podzorova S.A., Plakhova V.B., Shamova O.V., Orlov D.S., Kokriakov V.N. Endogenous defensin antibiotics as tentative regulators of sodium channels in spinal ganglion neurons Dokl. Akad. Nauk. 1997. V. 355 (5). P. 705–707 [In Russian].
  • Plakhova V.B., Rogachevskiy I.V., Shelykh T.N., Krylov B.V. A putative molecular analgesic effect of defensin peptide fragments // Med. Acad. Journal. 2013. V. 13 (3). P. 78–83 [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. 2003. V. 17 (1). P. 24–31 [In Russian].
  • Plakhova V.B., Rogachcvsky I.V., Shchegolev B.F., McKee M.L., Kokryakov V.N., Aleshina G.M., Podzorova S.A., Nozdrachev A.D., Ka-rymova E.A., Krylov B.V. Defensin NP-4 Decreases Voltage-sensitivity of Slow Sodium Channels in Sensory Neuron // Sensornye Sistemy. 2005. V. 19 (2). P. 110–116 [In Russian].
  • Plakhova V.B., Shchegolev B.F., Rogachevskii I.V., Nozdrachev A.D., Krylov B.V., Podzorova S.A., Kokriakov V.N. Putative molecular mechanism of defensin interaction with the membrane of the sensory neuron // Ross. Fiziol. Zh. Im. I.M. Sechenova. 2000. V. 86 (11). P. 1471–1480 [In Russian].
  • Rogachevskii I.V., Plakhova V.B., Shchegolev B.F., Nozdrachev A.D., Krylov B.V., Podzorova S.A., Kokryakov V.N. The defensin receptor: a possible mechanism responsible for reduced excitability of the neuronal sensory membrane. Dokl. Biol. Sci. V. 375. P. 595–598 [In Russian].
  • Almers W. Gating currents and charge movements in excitable membranes // Rev. Physiol. Biochem. Pharmacol. 1978. V. 82. P. 97–190.
  • Borovikova L., Borovikov D., Ermishkin V., Revenko S. The resistance of cutaneous feline C-fiber mechanoheat-sensitive unit termination to tetrodotoxin and its possible relation to tetrodotoxin-resistant sodium channels. Primary Sensory Neuron. 1997. V. 2. P. 65–75.
  • Elliott A.A., Elliott J.R. Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from mechanism of adult rat dorsal root ganglia // J. Physiol. (Lond.) 1993. V. 463. P. 39–56.
  • Gold M., Reichling D., Shuster M., Levine J. Hyperalgesic agents increase a tetrodotoxin-resistant Na current in nociceptors. Proc. Natl. Acad. Sci. USA. 1996. V. 93. N 3. P. 1108–1112.
  • 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 // Pflugers Arch. 1981. V. 391. N 1. P. 85–100.
  • 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. N 4. P. 449–472.
  • Kostyuk P.G., Veselovsky N.S., Tsyndrenko A.Y. Ionic currents in the somatic membrane of rat dorsal root ganglion neurons // Neuroscience. 1981. V. 6. N 12. P. 2423–2430.
  • 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. N 5528. P. 691–693.
  • Plakhova V., Rogachevsky I., Lopatina E., Shelykh T., Butkevich I., Mikhaienko 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. N 3–4. P. 55–64.
  • Schmidt M.W., Baldridge K.K., Boatz J.A., Elbert S.T., Gordon M.S., Jensen J.H., Koseki S., Matsunaga N., Nguyen K.A., Su S., Windus T.L., Dupuis M., Montgomery J.A. General atomic and molecular electronic structure system // J. Сomput. Сhemistry. 1993. V. 14. No 11. P. 1347–1363.
  • Shelykh T.N., Rogachevsky I.V., Nozdrachev A.D., Veselkina O.S., Podzorova S.A., Krylov B.V., Plakhova V.B. Molecular mechanism of modulation of nociceptive neuron membrane excitability by a tripeptide // Doklady Biochem. Biophys. 2016. V. 466. P. 77–80.
  • Waxman S.G., Cummins T.R., Dib-Hajj S.D., Black J.A. Voltage-gated sodium channels and the molecular pathogenesis of pain // J. Rehabil. Res. Dev. 2000. V. 37. N 5. P. 517–528.