In this paper, the changes in the frequency and amplitude of action potentials (PD) were investigated depending on the depolarization caused by the Ca2+ channels activity during the spontaneous synchronous activity (SSA) of hippocampal neurons in culture. Using the image analysis and patch-clamp we have shown that depolarization caused by the inhibitor of the GABA(A) receptor results in a mode of the spontaneous activity in which tonic high-frequency (2-3 Hz) APs are generated by a neuron without any changes in cytosolic free Ca2+ concentration, ([Ca2+]i). The tonic mode is interrupted burst activity, which is accompanied by a pulse of the slow depolarization and generation of calcium pulses. Inhibitor of T-type calcium channels ML218 inhibits this process. At the same time, the frequency and the amplitude of AP are regulated by slow depolarization pulses as follows: on the depolarization front, the APs frequency increases. At the same time, the amplitude decreases due to Na+ channels inactivation. The higher is the depolarization rate, the higher is the APs generation frequency. If slow depolarization amplitude exceeds Na+ channels reactivation potential, the neuronal impulse activity stops. As the cytoplasmic Ca2+ concentration ([Ca2+]i) increases and Ca2+-activated K+ channels are activated, depolarization amplitude decreases slowly, and Na+-channels are reactivated, which leads to a gradual increase in the amplitude of APs against the background of depolarization decrease. Termination of burst firing is due to [Ca2+]i increase and to Ca2+-dependent K+ channels activation, and voltage-gated Ca2+ channels (VGCC) inactivation. As a result, the membrane is hyperpolarized even more, that suppress AP generation, activate HCN channels and reactivate Na+ and VGCC. The activity of HCN-like channels increases, the membrane slowly depolarizes and the potential reaches critical, generation of tonic APs begins, with further opening of the Ca2+ channels, and Ca2+ potential and Ca2+ signal are generated again. Thus, the channels, determining the pulse of slow depolarization, control the frequency and the amplitude of APs of PD during SSA, regulating the activation and inactivation conditions of Na+ channels.
SSA - spontaneous synchronous activity, calcium impulse, T-type Ca2+- channels, voltage-gated calcium channels, action potential, genesis of bursting activity, bursting of action potential, depolarization shift, critical potential
1. Lu S.M., Guido W., Sherman S.M. Journal of Neuroscience, 1992, vol. 68 (6), pr. 2185-98.
2. Anava S., Greenbaum A., Ben Jacob E., Hanein Y., Ayali A. Biophys. J., 2009, vol. 96 (4), pr. 1661-1670.
3. Kononov A.V., Ball N.V., Zinchenko V.P. Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology, 2011, vol. 5 (2), pr. 162-170.
4. McCormick D.A., Contreras D. On Annu. Rev. Physiol., 2001, vol. 63, pr. 815-46.
5. Nikonenko I., Bancila M., Bloc A., Muller D., Bijlenga P. Mol Pharmacol., 2005, vol. 68 (1), pr. 84-9.
6. Kopecky B.J., Liang R., Bao J. Pflugers Arch., 2014, vol. 466 (4), pr. 757-765.
7. Nilius B., Tala K., Verkhratsky A. Cell Calcium., 2006, vol. 40 (2), pr. 81-88.
8. Kim D., Song I., Keum S., Lee T., Jeong M-J, Kim S-S, et al. Neuron., 2001, vol. 31 (1), pr. 35-45.
9. Song I., Kim D., Choi S., Sun M., Kim Y., Shin H.S. J. Neurosci., 2004, vol. 24 (22), pr. 5249-5257.
10. Huc S., Monteil A., Bidaud I., Barbara G., Chemin J., Lory P. Biochimica et Biophysica Acta., 2009, vol. 1793 (6), pr. 947-952.
11. Perez-Reyes [et al.] Cell. Mol. Life Sci., 1999, vol. 56 (7-8), pr. 660-9.
12. Chevalier M., Lory P., Mironneau C., Macrez N., Quignard J.F. Eur. J. Neurosci., 2006, vol. 23 (9), pr. 2321-9.
13. Proft J., Weiss N.G. Molecular Pharmacology, June 2015, vol. 87 (6), pr. 890-906.
14. Perez-Reyes E. Mol. Pharmacol., 2010, vol. 77 (2), pr. 136-8.
15. Sánchez-Alonso J.L., Halliwell J.V., Colino A. Neurosci. Lett., 2008, vol. 439 (3), pr. 275-80.
16. Iyer R., Ungless M.A., Faisa A.A. Sci. Rep., 2017, vol. 7 (1), pr. 5248.
17. Rehak R., Bartoletti T.M., Engbers J.D.T., Berecki G., Turner R.W., Zamponi G.W. Plos One, 2013, vol. 8, e61844, DOI:https://doi.org/10.1371/journal.pone.0061844.
18. Wolfart J., Roeper J. J. Neurosci., 2002, vol. 22 (9), pr. 3404-3413.
19. Xu J., Clancy C.E. Plos One, 2008, vol. 3 (4), p. e2056, DOI:https://doi.org/10.1371/journal.pone.0002056.
20. Wolfe J.T., Wang H., Perez-Reyes E., Barrett P.Q. J. Physiol., 2002, vol. 538 (2), pr. 343-355.
21. Chemin J., Mezghrani A., Bidaud I., Dupasquier S., Marger F., Barrère C. [et al.] J. Biol. Chem., 2007, vol. 282 (45), pr. 32710-32718.
22. Chemin J., Monteil A., Perez-Reyes E., Nargeot J., Lory P. EMBO J., 2001, vol. 20 (24), pr. 7033-7040.
23. Chemin J., Nargeot J., Lory P. J. Biol. Chem., 2007, vol. 282 (4), pr. 2314-2323.
24. Talavera K., Staes M., Janssens A., Droogmans G., Nilius B. J. Gen. Physiol., 2004, vol. 124 (3), pr. 225-238.
25. Zhang Y., Cribbs L.L., Satin J. Am. J. Physiol. Heart Circ. Physiol., 2000, vol. 278 (1), pr. H184-H193.
26. Wolfe J.T., Wang H., Howard J., Garrison J.C., Barrett P.Q. Nature., 2003, vol. 424 (6945), pr. 209-213.
27. Tao J., Hildebrand M.E., Liao P., Liang M.C., Tan G., Li S. [et al.] Mol. Pharmacol., 2008, vol. 73 (6), pr. 1596-1609.
28. Hildebrand M.E., David L.S., Hamid J., Mulatz K., Garcia E., Zamponi G.W., Snutch T.P. J. Biol. Chem., 2007, vol. 282 (29), pr. 21043-55.
29. Nelson M.T., Todorovic S.M., Perez-Reyes E. Current Pharmaceutical Design., 2006, vol. 12 (18), pr. 2189-97.
30. Todorovic S.M., Jevtovic-Todorovic V. Pflügers Archiv., 2014, vol. 466 (4), pr. 701-6.
31. Kopecky B.J., Liang R., Bao J. European journal of physiology, 2014, vol. 466 (4), pr. 757-765.
32. Orestes P., Bojadzic D., Chow R.M., Todorovic S.M. Molecular pharmacology, 2009, vol. 75 (3), pr. 542-554.
33. Spitzer N.C., Olson E.X. J. Neurobiol., 1995, vol. 26 (3), pr. 316-324.
34. Robinson H.P., Kawahara M. [et al.] J. Neurophysiol., 1993, vol. 70 (4), pr. 1606-1616.
35. Guzman J.N., Sánchez-Padilla J., Chan C.S., Surmeier D.J. J. Neurosci., 2009, vol. 29 (35), pr. 11011-9.
36. Surmeier D.J., Schumacker P.T. J. Biol. Chem., 2013, vol. 288 (15), pr. 10736-10741.
37. Lieberman O.J., Choi S.J., Kanter E., Saverchenko A., Frier M.D., Fiore G.M., Wu M., Kondapalli J., Zampese E., Surmeier D.J., Sulzer D., Mosharov E.V. eNeuro, 2017, vol. 4 (6), pr. 0167-17.
38. Surmeier D.J., Obeso J.A., Halliday G.M. Nat. Rev. Neurosci., 2017, vol. 18 (2), pr. 101-113.
39. Chan C.S., Guzman J.N., Ilijic E., Mercer J.N., Rick C., Tkatch T., Meredith G.E., Surmeier D.J. Nature, 2007, vol. 447 (7148), pr. 1081-6.
40. Grynkiewicz G., Poenie M., Tsien R.Y. J. Biol. Chem., 1985, vol. 260 (6), pr. 3440-50.
41. Hayashi H., Miyata H., Terada H., Satoh H., Katoh H., Nakamura T., Kobayashi A. Jpn. Heart J., 1994, vol. 35 (5), pr. 673-82.
42. Cozzi L., D’Angelo P., Sanguineti V. Biol. Cybern., 2006, vol. 94 (5), pr. 335-349
43. Cain S.M., Snutch T.P. Biochimica et Biophysica Acta, 2013, vol. 1828 (7), pr. 1572.
44. Turovsky E.A., Turovskaya M.V., Gaidin S.G., Zinchenko V.P. Arch. Biochem. Biophys., 2017, vol. 615, pr. 35-43.
45. Turovsky E.A., Zinchenko V.P., Gaidin S.G., Turovskaya M.V. Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology, 2018, vol. 12, pr. 74-84.
46. Zinchenko V.P., Turovskaya M.V., Teplov I.Yu., Berezhnov A.V., Turovsky E.A. Biophysics, 2016, vol. 61 (1), pr. 85-93
47. Izhikevich E.M. International Journal of Bifurcation and Chaos, 2000, vol. 10 (6), pr. 1171-1266.
48. Robinson H.P., Torimitsu K., Jimbo Y., Kuroda Y., Kawana A. Jpn. J. Physiol., 1993, vol. 43 (1), pr. 25-30.
49. Dynnik V.V., Kononov A.V., Sergeev A.V., Teplov I.Yu., Zinchenko V.P. Plos One, 2015, vol. 10 (7), p. e0134145, DOI:https://doi.org/10.1371/journal.pone.0134145.
50. Cooper D. Neurochemistry international, 2002, vol. 41 (5), pr. 333-340.
51. Swadlow H.A., Gusev A.G., Bezdudnaya T. Journal of Neuroscience, 2002, vol. 22 (17), pr. 7766-7773.
52. Zinchenko V.P., Turovsky E.A., Turovskaya M.V., Berezhnov A.V., Sergeev A.I., Dynnik V.V. Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology, 2016, vol. 10 (2), pr. 118-125.
53. Zinchenko V.P., Gaidin S.G., Teplov I.Y., Kosenkov A.M. Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology, 2017, vol. 11 (4), pr. 261-274.
