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Cholinergic Modulation of Acetylcholine Secretion at the Neuromuscular Junction

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Abstract

The effect of cholinergic compounds (activators and blockers of nicotinic cholinergic receptors) on acetylcholine secretion from motor nerve endings is of interest in relation with the issue of the presence of the feedback mechanism in the neuromuscular synapse. It is assumed that nerve endings may have autoreceptors to acetylcholine, and that changes in their activity affect the release of the neurotransmitter in response to nerve stimulation. However, numerous experimental data do not give an unambiguous idea on the targeting and mechanisms of action of both endogenous acetylcholine and other cholinergic compounds on the evoked quantal release of acetylcholine in the neuromuscular synapse. The relevance of such studies is due to the need to unravel the effects of these compounds, since many of them are being used in clinical practice. The review is devoted to the analysis of results obtained on the classical object of neurophysiology, a neuromuscular preparations of warm-blooded animals, using a radioisotope method to assess the amount of a neurotransmitter secreted from nerve endings and an electrophysiological method to determine the number of quanta released in response to nerve stimulation. We compare numerous data obtained through the use of the activators and blockers of ionotropic nicotinic receptors, as well as the probable mechanisms of action of cholinergic compounds that modulate the secretory process. A schematic diagram of the regulation of quantal secretion is proposed, given the new data on the possible involvement of Schwann cell and presynaptic homeostatic plasticity.

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REFERENCES

  1. Kamenskaya, M.A., Magazanik, L.G., Kotova, E.R., Samybaldina, N.K., Miroshnikov, A.I., and Apsalon, U.R., Effect of presynaptic neurotoxins from bee and cobra venom on spontaneous mediator secretion from mouse motor-nerve ending, Bull. Exp. Biol. Med., 1979, vol. 87(5), pp. 402–405. https://doi.org/10.1007/BF00806665

  2. Magazanik, L.G. and Nikol’ski, E.E., Pre- and postsynaptic action of a cholinomimetic (subecholine) under a voltage clamp of the postsynaptic membrane, Dokl. Akad. Nauk. SSSR, 1979, vol. 249(6), pp. 1488–1491.

  3. Magazanik, L.G., Potapjeva, N.N., and Fedorova, I.M., Modulation of transmitter release from motor nerve endings by muscarinic and adenosine receptors, J. Neurochem., 1998, vol. 71, p. S4.

  4. Nikolsky, E.E., Vyskocil, F., Bukharaeva, E.A., Samigullin, D., and Magazanik, L.G., Cholinergic regulation of the evoked quantal release at frog neuromuscular junction, J. Physiol., 2004, vol. 560, pp. 77–88. https://doi.org/10.1113/jphysiol.2004.065805.4

  5. Bukharaeva, E.A., Samigullin, D., Nikolsky, E.E., and Magazanik, L.G., Modulation of the kinetics of evoked quantal release at mouse neuromuscular junctions by calcium and strontium, J. Neurochem., 2007, vol. 100(4), pp. 939–949. https://doi.org/10.1111/j.1471-4159.2006.04282.x

  6. Santafe, M.M., Salon, I., Garcia, N., Lanuza, M.A., Uchitel, O.D., and Tomas, J., Modulation of ACh release by presynaptic muscarinic autoreceptors in the neuromuscular junction of the newborn and adult rat, Eur. J. Neurosci., 2003, vol. 17(1), pp. 119–127. https://doi.org/10.1046/j.1460-9568.2003.02428.x

  7. Khaziev, E.F., Fatikhov, N.F., Samigullin, D.V., Barrett, G.L., Bukharaeva, E.A., and Nikolsky, E.E., Decreased entry of calcium into motor nerve endings upon activation of presynaptic cholinergic receptors, Dokl. Biol. Sci., 2012, vol. 446, pp. 283–285. https://doi.org/10.1134/S0012496612050080

  8. Connor, E.A., Dunaevsky, A., Griffiths, D.J., Hardwick, J.C., and Parsons, R.L., Transmitter release differs at snake twitch and tonic endplates during potassium-induced nerve terminal depolarization, J. Neurophysiol., 1997, vol. 77(2), pp. 749–760. https://doi.org/10.1152/jn.1997.77.2.749

  9. Foldes, F.F., Chaudhry, I.A., Kinjo, M., and Nagashima, H., Inhibition of mobilization of acetylcholine: the weak link in neuromuscular transmission during partial neuromuscular block with d-tubocurarine, Anesthesiology, 1989, vol. 71, pp. 218–223.

  10. Somogyi, G.T., Vizi, E.S., Chaudhry, I.A., Nagashima, H., Duncalf, D., Foldes, F.F., and Goldiner, P.L., Modulation of stimulation-evoked release of newly formed acetylcholine from mouse hemidiaphragm preparation, Naunyn Schmiedebergs Arch. Pharmacol., 1987, vol. 336(1), pp. 11–15. https://doi.org/10.1007/BF00177744

  11. Katz, B., and Miledi, R., Estimates of quantal content during 'chemical potentiation’ of transmitter release, Proc. R. Soc. Lond. B. Biol. Sci., 1979, vol. 205(1160), pp. 369–378. https://doi.org/10.1098/rspb.1979.0070

  12. Li, R.A., Ennis, I.L., Velez, P., Tomaselli, G.F., and Marban, E., Novel structural determinants of mu-conotoxin (GIIIB) block in rat skeletal muscle (mu1) Na+channels, J. Biol. Chem., 2000, vol. 275(36), pp. 27551–27558. https://doi.org/10.1074/jbc.M909719199

  13. Wessler, I., Halank, M., Rasbach, J., and Kitbinger, H., Presynaptic nicotine receptors mediating a positive feed-back on transmitter release from the rat phrenic nerve, Naunyn-Schmiedebergs Arch. Pharmacol., 1986, vol. 334, pp. 365–372. ttps://doi.org/10.1007/BF00569371

  14. Wessler, I., Apel, C., Garmsen, M., and Klein, A., Effects of nicotine receptor agonists on acetylcholine release from the isolated motor nerve, small intestine and trachea of rats and guineapigs, Clin. Investig., 1992, vol. 70(3–4), pp. 182–189. https://doi.org/10.1007/BF00184649

  15. Wessler, I., Scheuer, B., and Kilbinger, H., [3H]acetylcholine release from the phrenic nerve is increased or decreased by activation or desensitization of nicotine receptors, Eur. J. Pharmacol., 1987, vol. 135(1), pp. 85–87. https://doi.org/10.1016/0014-2999(87)90760-6

  16. Giniatullin, R.A. and Magazanik, L.G., Does desensitisation of acetylcholine receptors play a physiological role in the neuromuscular synapse? Ross. Fiziol. Zh. im. I.M. Sechenova, 1998, vol. 84(1–2), pp. 3–14.

  17. Wilson, D.F., Influence of presynaptic receptors on neuromuscular transmission in rat, Am. J. Physiol., 1982, vol. 242(5), pp. 366–372. https://doi.org/10.1152/ajpcell.1982.242.5.C366

  18. Prior, C., Dempster, J., and Marshall, I.G., Electrophysiological analysis of transmission at the skeletal neuromuscular junction, J. Pharmacol. Toxicol. Met., 1993, vol. 30, pp. 1–17. https://doi.org/10.1016/1056-8719(93)90002-V

  19. Prior, C. and Singh, S., Factors influencing the low-frequency associated nicotinic ACh autoreceptor-mediated depression of ACh release from rat motor nerve terminals, Br. J. Pharmacol., 2000, vol. 129(6), pp. 1067–1074. https://doi.org/10.1038/sj.bjp.0707442

  20. Singh, S., and Prior, C., Prejunctional effects of the nicotinic ACh receptor agonist dimethylphenylpiperazinium at the rat neuromuscular junction, J. Physiol., 1998, vol. 511, pp. 451–560. https://doi.org/10.1111/j.1469-7793.1998.451bh.x

  21. Balezina, O.P., Fedorin, V.V., and Gaidukov, A.E., Effect of nicotine on neuromuscular transmission in mouse motor synapses, Bull. Exp. Biol. Med., 2006, vol. 142(1), pp. 17–21. https://doi.org/10.1007/s10517-006-0280-32006

  22. Gaydukov, A.E., Bogacheva, P.O., Tarasova, E.O., and Balezina, O.P., The mechanism of choline-mediated inhibition of acetylcholine release in mouse motor synapses, Acta Naturae, 2014, vol. 6(4), pp. 110–115. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273098/pdf/AN20758251-23-110.pdf

  23. Apel, C., Ricny, J., Wagner, C., and Wessler, I., alpha-Bungarotoxin, kappa-bungarotoxin, alpha-cobratoxin and erabutoxin-b do not affect [3H]acetylcholine release from the rat isolated left hemidiaphragm, Naunyn Schmiedebergs Arch. Pharmacol., 1995, vol. 352(6), pp. 646–652. https://doi.org/10.1007/BF00171324

  24. Vizi, E.S., Chaudhry, I.A., Goldiner, P.L., Ohta, Y., Nagashima, H., and Foldes, F.F., The pre- and postjunctional components of the neuromuscular effect of antibiotics, J. Anesth., 1991, vol. 5(1), pp. 1–9. https://doi.org/10.1007/s0054010050001

  25. Vizi, E.S., Somogyi, G.T., Nagashima, H., Duncalf, D., Chaudhry, I.A., Kobayashi, O., Goldiner, P.L., and Foldes, F.F., Tubocurarine and pancuronium inhibit evoked release of acetylcholine from the mouse hemidiaphragm preparation, Br. J. Anaesth., 1987, vol. 59(2), pp. 226–231. https://doi.org/10.1093/bja/59.2.226

  26. Faria, M., Oliveira, L., Timoteo, M.A., Lobo, M.G., and Correia-De-Sa, P., Blockade of neuronal facilitatory nicotinic receptors containing alpha 3 beta 2 subunits contribute to tetanic fade in the rat isolated diaphragm, Synapse, 2003, vol. 49, pp. 77–88. https://doi.org/10.1002/syn.10211

  27. Vizi, E.S. and Somogyi, G.T., Prejunctional modulation of acetylcholine release from the skeletal neuromuscular junction: link between positive (nicotinic)-and negative (muscarinic)-feedback modulation, Br. J. Pharmacol., 1989, vol. 97(1), pp. 65–70. https://doi.org/10.1111/j.1476-5381.1989.tb11924.x

  28. Wessler, I., Acetylcholine at motor nerves: storage, release, and presynaptic modulation by autoreceptors and adrenoceptors, Int. Rev. Neurobiol., 1992, vol. 34, pp. 283–384. https://doi.org/10.1016/s0074-7742(08)60100-2

  29. Kimura, I., Okazaki, M., Uwano, T., Kobayashi, S., and Kimura, M., Succinylcholine-induced acceleration and suppression of electrically evoked acetylcholine release from mouse phrenic nerve-hemidiaphragm muscle preparation, Jpn. J. Pharmacol., 1991, vol. 57(3), pp. 397–403. https://doi.org/10.1254/jjp.57.397

  30. Tian, L., Prior, C., Dempster, J., and Marshall, I.G., Nicotinic antagonist-produced frequencydependent changes in acetylcholine release from rat motor nerve terminals, J. Physiol., 1994, vol. 476(3), pp. 517–529. https://doi.org/10.1113/jphysiol.1994.sp020151

  31. Ferry, C.B. and Kelly, S.S., The nature of the presynaptic effects of (+)-tubocurarine at the mouse neuromuscular junction, J. Physiol., 1988, vol. 403, pp. 425–437. https://doi.org/10.1113/jphysiol.1988.sp017257

  32. Wilson, D.F., Influence of presynaptic receptors on neuromuscular transmission in rat, Am. J. Physiol., 1982, vol. 242, pp. 366–373. https://doi.org/10.1152/ajpcell.1982.242.5.C366

  33. Wilson, D.F. and Thomsen, R.H., Nicotinic receptors on the rat phrenic nerve: evidence for negative feedback, Neurosci. Lett., 1991, vol. 132(2), pp. 163–166. https://doi.org/10.1016/0304-3940(91)90292-2

  34. Tian, L., Prior, C., Dempster, J., and Marshall, I.G., Hexamethonium- and methyllycaconitineinduced changes in acetylcholine release from rat motor nerve terminals, Br. J. Pharmacol., 1997, vol. 122(6), pp. 1025–1034. https://doi.org/10.1038/sj.bjp.0701481

  35. Wilson, D.F. and Thomsen, R.H., Effects of hexamethonium on transmitter release from the rat phrenic nerve, Neurosci. Lett., 1992, vol. 143(1–2), pp. 79–82. https://doi.org/10.1016/0304-3940(92)90237-2

  36. Wilson, D.F., West, A.E., and Lin, Y., Inhibitory action of nicotinic antagonists on transmitter release at the neuromuscular junction of the rat, Neurosci. Lett., 1995, vol. 186(1), pp. 29–32. https://doi.org/10.1016/0304-3940(95)11274-Z

  37. Domet, M.A., Webb, C.E., and Wilson, D.F., Impact of alpha-bungarotoxin on transmitter release at the neuromuscular junction of the rat, Neurosci. Lett., 1995, vol. 199(1), pp. 49–52. https://doi.org/10.1016/0304-3940(95)12013-t

  38. Prior, C., Tian, L., Dempster, J., and Marshall, I.G., Prejunctional actions of muscle relaxants: Synaptic vesicles and transmitter mobilization as sites of action, Gen. Pharmacol., 1995, vol. 26, pp. 659–666. https://doi.org/10.1016/0306-3623(94)00246-j

  39. Bowman, W.C., Prior, C., and Marshall, I.G., Presynaptic Receptors in the Neuromuscular Junction, Ann. N. Y. Acad. Sci., 1990, vol. 604, pp. 69–81. https://doi.org/10.1111/j.1749-6632.1990.tb31983.x

  40. Bowman, W.C., Marshall, L.G., Gibb, A.G., and Harbome, A.J., Feedback control of transmitter release at the neuromuscular junction, Trends. Pharmacol. Sci., 1988, vol. 9, pp. 16–20.

  41. Jones, W. and Salpeter, M., Absence of [125I] alpha-bungarotoxin binding to motor nerve terminals of frog, lizard and mouse muscle, J. Neurosci., 1983, vol. 3(2), pp. 326–331. https://doi.org/10.1523/JNEUROSCI.03-02-00326

  42. Tsuneki, H., Kimura, I., Dezaki, K., Kimura, M., Sala, C., and Fumagalli, G., Immunohistochemical localization of neuronal nicotinic receptor subtypes at the pre- and postjunctional sites in mouse diaphragm muscle, Neurosci. Lett., 1995, vol. 196, pp. 13–16. https://doi.org/10.1016/0304-3940(95)11824-G

  43. Petrov, K.A., Girard, E., Nikitashina, A.D., Colasante, C., Bernard, V., Nurullin, L., Leroy, J., Samigullin, D., Colak, O., Nikolsky, E., Plaud, B., and Krejci, E., Schwann cells sense and control acetylcholine spillover at the neuromuscular junction by α7 nicotinic receptors and butyrylcholinesterase, J. Neurosci., 2014, vol. 34(36), pp. 11870–11883. https://doi.org/10.1523/JNEUROSCI.0329-14.2014

  44. Fagerlund, M.J. and Eriksson, L.I., Current concepts in neuromuscular transmission, Br. J. Anaesth., 2009, vol. 103(1), pp. 108–114. https://doi.org/10.1093/bja/aep150

  45. Jonsson, M., Gurley, D., Dabrowski, M., Larsson, O., Johnson, E.C., and Eriksson, L.I., Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade, Anesthesiology, 2006, vol. 105(3), pp. 521–533. https://doi.org/10.1097/00000542-200609000-00016

  46. Wessler, I., Control of transmitter release from the motor nerve by presynaptic nicotinic and muscarinic autoreceptors, Trends Pharmacol. Sci., 1989, vol. 10(3), pp. 110–114. https://doi.org/10.1016/0165-6147(89)90208-3

  47. Vizi, E.S., Kiss, J., and Elenkov, I.J., Presynaptic modulation of cholinergic and noradrenergic neurotransmission: interaction between them, NIPS, 1991, vol. 6, pp. 119–123.

  48. Miledi, R., Molenaar, P.C., and Polak, R.L., Alpha-Bungarotoxin enhances transmitter “released” at the neuromuscular junction, Nature, 1978, vol. 272(5654), pp. 641–643. https://doi.org/10.1038/272641a0

  49. Kabbani, N. and Nichols, R.A., Beyond the Channel: Metabotropic Signaling by Nicotinic Receptors, Trends Pharmacol. Sci., 2018, vol. 39(4), pp. 354–366. https://doi.org/10.1016/j.tips.2018.01.002

  50. Tsuneki, H., Klink, R., Lena, C., Korn, H., and Changeux, J.P., Calcium mobilization elicited by two types of nicotinic acetylcholine receptors in mouse substantia nigra pars compacta, Eur. J. Neurosci., 2000, vol. 12(7), pp. 2475–2485. https://doi.org/10.1046/j.1460-9568.2000.00138.x

  51. Djemil, S., Chen, X., Zhang, Z., Lee, I., Rauf, M., Pak, D., and Dzakpasu, R., Activation of nicotinic acetylcholine receptors induces potentiation and synchronization within in vitro hippocampal networks, J. Neurochem., 2020, vol. 153(4), pp. 468–484. https://doi.org/10.1111/jnc.14938

  52. Mukhamedyarov, M., Kochunova, J., and Yusupova, E., The contribution of calcium/calmodulin-dependent protein-kinase II (CaMKII) to short-term plasticity at the neuro-muscular junction, Brain Res. Bull., 2010, vol. 81(6), pp. 613–616. https://doi.org/10.1016/j.brainresbull.2009.12.010

  53. Kulak, J.M., McIntosh, J.M., Yoshikami, D., and Olivera, B.M., Nicotine-evoked transmitter release from synaptosomes: functional association of specific presynaptic acetylcholine receptors and voltage-gated calcium channels, J. Neurochem., 2001, vol. 77(6), pp. 1581–1589. https://doi.org/10.1046/j.1471-4159.2001.00357.x

  54. Bowman, W.C., Presynaptic nicotinic autoreceptors, Trends Pharmacol. Sci., 1989, vol. 10(4), pp. 136–137. https://doi.org/10.1016/0165-6147(89)90162-4

  55. Tarasova, E.O., Gaydukov, A.E., and Balezina, O.P., Methods of activation and the role of calcium/calmodulin-dependent protein kinase II in the regulation of acetylcholine secretion in the motor synapses of mice, Neurochem. J., 2015, vol. 9(2), pp. 101–107. https://doi.org/10.1134/S1819712415020099

  56. Gaydukov, A.E. and Balezina, O.P., CaMKII Is Involved in the Choline-Induced Downregulation of Acetylcholine Release in Mouse Motor Synapses, Acta Naturae, 2017, vol. 9(4), pp. 110–113.

  57. Gaydukov, A.E., Bogacheva, P.O., and Balezina, O.P., The Participation of Presynaptic Alpha7 Nicotinic Acetylcholine Receptors in the Inhibition of Acetylcholine Release during Long-Term Activity of Mouse Motor Synapses, Neurochem. J., 2019, vol. 13(1), pp. 20–27. https://doi.org/10.1134/S1819712419010082

  58. Shen, J.X. and Yakel, J.L., Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system, Acta Pharmacol. Sin., 2009, vol. 30(6), pp. 673–680. https://doi.org/10.1038/aps.2009.64

  59. King, J.R., Ullah, A., Bak, E., Jafri, M.S., and Kabbani, N., Ionotropic and metabotropic mechanisms of allosteric modulation of α7 nicotinic receptor intracellular calcium, Mol. Pharmacol., 2018, vol. 93, pp. 601–661. https://doi.org/10.1124/mol.117.111401

  60. Penner, R. and Dreyer, F., Two different presynaptic calcium currents in mouse motor nerve terminals, Pfugers Arch., 1986, vol. 406, pp. 190–197. https://doi.org/10.1007/BF00586682

  61. Wood, S.J. and Slater, C.R., Safety factor at the neuromuscular junction, Prog. Neurobiol., 2001, vol. 64(4), pp. 393–429. https://doi.org/10.1016/s0301-0082(00)00055-1

  62. Zhangsun, D., Zhu, X., Wu, Y., Hu, Y., Kaas, Q., Craik, D.J., McIntosh, J.M., and Luo, S., Key residues in the nicotinic acetylcholine receptor β2 subunit contribute to α-conotoxin LvIA binding, J. Biol. Chem., 2015, vol. 290(15), pp. 9855–9862. https://doi.org/10.1074/jbc.M114.632646

  63. Petrov, K.A., Malomouzh, A.I., Kovyazina, I.V., Krejci, E., Nikitashina, A.D., Proskurina, S.E., Zobov, V.V., and Nikolsky, E.E., Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N-methyl-D-aspartate receptor activation, Eur. J. Neurosci., 2013, vol. 37(2), pp. 181–189. https://doi.org/10.1111/ejn.12029

  64. Noronha-Matos, J.B., Oliveira, L., Peixoto, A., Almeida, L., Castellao-Santana, M.L., Ambiel, C.R., Alves-do Prado, W., and Correia-de-Sa, P., Nicotinic α7 receptor-induced adenosine release from perisynaptic Schwann cells controls acetylcholine spillover from motor endplates, J. Neurochem., 2020, vol. 154(3), pp. 263–283. https://doi.org/10.1111/jnc.14975

  65. Correia-de-Sa, P., Sebastiao, A.M., and Ribeiro, J.A., Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve ending of the rat, Br. J. Pharmacol., 1991, vol. 103, pp. 1614–1620. https://doi.org/10.1111/j.1476-5381.1991.tb09836.x

  66. Wang, X., McIntosh, J.M., and Rich, M.M., Muscle Nicotinic Acetylcholine Receptors May Mediate Trans-Synaptic Signaling at the Mouse Neuromuscular Junction, J. Neurosci., 2018, vol. 38(7), pp. 1725–1736. https://doi.org/10.1523/JNEUROSCI.1789-17.2018

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ACKNOWLEDGMENTS

The authors are grateful to Drs. V.F. Khuzakhmetova and A.N. Tsentsevitsky for helpful discussions and valuable recommendations on the manuscript.

Funding

Writing of this review was supported by the Russian Scientific Foundation (project. No. 18-15-00046). A.I. Skorinkin was supported was supported by government assignment to the FRC Kazan Scientific Center of the Russian Academy of Sciences.

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    E. A. Bukharaeva & A. I. Skorinkin

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E.A. Bukharaeva: paper’s basic idea, literature data collection, manuscript writing; A.I. Skorinkin: discussion, manuscript writing and editing.

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Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, Nos. 4–5, pp. 458–473https://doi.org/10.31857/S0869813921040063.

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Bukharaeva, E.A., Skorinkin, A.I. Cholinergic Modulation of Acetylcholine Secretion at the Neuromuscular Junction. J Evol Biochem Phys 57, 372–385 (2021). https://doi.org/10.1134/S0022093021020174

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