Skip to main content
SpringerLink
Log in

Changes in the Parameters of Quantal Acetylcholine Release after Activation of PAR1-Type Thrombin Receptors at the Mouse Neuromuscular Junctions

  • Articles
  • Published:
Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

In mature and newly formed neuromuscular synapses of mouse skeletal muscles, miniature endplate potentials (MEPPs) and multiquantal endplate potentials (EPPs) evoked by a single stimulation of the nerve were recorded using intracellular microelectrode technique. The mechanisms underlying the changes in spontaneous and evoked acetylcholine (ACh) release caused by the activation of PAR1-type muscle receptors induced by their peptide agonist TRAP6-NH2 were studied. It has been shown for the first time that, in either mature or newly formed motor synapses, the activation of PAR1 that lack presynaptic localization causes a sustained increase in the MEPP amplitude due to the increase in the ACh quantal size at the presynaptic level. It was found that phospholipase C (PLC) participates in the signaling mechanism triggered by the PAR1 activation. Exogenously applied brain-derived neurotrophic factor (BDNF) mimics the effect of activation of PAR1 by TRAP6-NH2. Moreover, an increase in the MEPP amplitude caused by the peptide PAR1 agonist was fully prevented by blocking the BDNF receptors–tropomyosin receptor kinases B (TrkB). Thus, it has been shown for the first time that the increase in ACh quantal size due to the activation of PAR1 in motor synapses is mediated by a complex signaling cascade that starts at the postsynaptic level of the motor synapse and ends at the presynaptic level. It is expected that the activation of PAR1 at the muscle fiber membrane followed by the PLC upregulation results in the release of neurotrophin BDNF as a retrograde signal. Its effect on the presynaptic TrkB receptors triggers the cascade leading to an increase in the quantal size of ACh.

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

Access this article

Log in via an institution

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

References

  1. Trejo J. 2003. Protease-activated receptors: New concepts in regulation of G protein-coupled receptor signaling and trafficking. J. Pharmacol. Exp. Ther. 307, 437–442.

    Article  PubMed  CAS  Google Scholar 

  2. Ossovskaya V.S., Bunnett N.W. 2004. Protease-activated receptors: Contribution to physiology and disease. Physiol. Rev. 84, 7–14.

    Article  Google Scholar 

  3. McLaughlin J.N., Shen L., Holinstat M., Brooks J.D., DiBenedetto, E., Hamm, H.E. 2005. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. J. Biol. Chem. 280, 25048–25059.

    Article  PubMed  CAS  Google Scholar 

  4. Zhao P., Metcalf M., Bunnett N.W. 2014. Biased signaling of protease-activated receptors. Front. Endocrinol. (Lausanne). 5, 67.

    Google Scholar 

  5. Luo W., Wang Y., Reiser G. 2007. Protease-activated receptors in the brain: Receptor expression, activation, and functions in neurodegeneration and neuroprotection. Brain Res. Rev. 56, 331–345.

    Article  PubMed  CAS  Google Scholar 

  6. Gieseler F., Ungefroren H., Settmacher U., Hollenberg M.D., Kaufmann R. 2013. Proteinase-activated receptors (PARs)–focus on receptor-receptor-interactions and their physiological and pathophysiological impact. Cell Commun. Signal. 11, 86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Almonte A.G., Sweatt J.D. 2011. Serine proteases, serine protease inhibitors, and protease-activated receptors: Roles in synaptic function and behavior. Brain Res. 1407, 107–122.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Alberelli M.A., De Candia E. 2014. Functional role of protease activated receptors in vascular biology. Vascul. Pharmacol. 62, 72–81.

    Article  PubMed  CAS  Google Scholar 

  9. Ramachandran R., Altier C., Oikonomopoulou K., Hollenberg M.D. 2016. Proteinases, their extracellular targets, and inflammatory signaling. Pharmacol. Rev. 68, 1110–1142.

    Article  PubMed  CAS  Google Scholar 

  10. Ben Shimon M., Lenz M., Ikenberg B., Becker D., Shavit Stein E., Chapman J., Tanne D., Pick C.G., Blatt I., Neufeld M., Vlachos A., Maggio N. 2015. Thrombin regulation of synaptic transmission and plasticity: Implications for health and disease. Front. Cell. Neurosci. 9, 151.

    PubMed  PubMed Central  Google Scholar 

  11. Lanuza M.A., Garcia N., González C.M., Santafé M.M., Nelson P.G., Tomas J. 2003. Role and expression of thrombin receptor PAR-1 in muscle cells and neuromuscular junctions during the synapse elimination period in the neonatal rat. J. Neurosci. Res. 73, 10–21.

    Article  PubMed  CAS  Google Scholar 

  12. Lanuza M.A., Besalduch N., Garcia N., Sabaté M., Santafé M.M., Tomàs J. 2007. Plastic-embedded semithin cross-sections as a tool for high-resolution immunofluorescence analysis of the neuromuscular junction molecules: Specific cellular location of protease-activated receptor-1. J. Neurosci. Res. 85, 748–756.

    Article  PubMed  CAS  Google Scholar 

  13. Festoff B.W., Suo Z., Citron B.A. 2001. Plasticity and stabilization of neuromuscular and CNS synapses: Interactions between thrombin protease signaling pathways and tissue transglutaminase. Int. Rev. Cytol. 211, 153–177.

    Article  PubMed  CAS  Google Scholar 

  14. Balezina O.P., Gerasimenko N.Y., Dugina T.N., Strukova S.M. 2005. Study of neurotrophic activity of thrombin on the model of regenerating mouse nerve. Bull. Exp. Biol. Med. 139, 4–6.

    Article  PubMed  CAS  Google Scholar 

  15. Balezina O.P., Gerasimenko N.Y., Strukova S.M. 2007. Effect of PAR1 agonist on acetylcholine secretion in a newly formed neuromuscular synapse in mice. Bull. Exp. Biol. Med. 144, 653–656.

    Article  PubMed  CAS  Google Scholar 

  16. Bogatcheva P.O., Balezina O.P. 2013. Multidirectional effects of calmodulin kinase II on transmitter release in mature and newly formed mouse motor synapses. Bull. Exp. Biol. Med. 154, 316–319.

    Article  PubMed  CAS  Google Scholar 

  17. Tarasova E.O., Miteva A.S., Gaydukov A.E., Balezina O.P. 2015. The role of adenosine receptors and L-type calcium channels in the regulation of the mediator secretion in mouse motor synapses. Biochem. (Moscow) Suppl. Ser. A: Membr. Cell Biol. 9, 318–328.

    Article  Google Scholar 

  18. Gaydukov A.E., Bogacheva P.O., Balezina O.P. 2016. Calcitonin gene-related peptide increases acetylcholine quantal size in neuromuscular junctions of mice. Neurosci. Lett. 628, 17–23.

    Article  PubMed  CAS  Google Scholar 

  19. McLachlan E. M., Martin A.R. 1981. Non-linear summation of end-plate potentials in the frog and mouse. J. Physiol. 311, 307–324.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Fujita T., Liu T., Nakatsuka T., Kumamoto E. 2009. Proteinase-activated receptor-1 activation presynaptically enhances spontaneous glutamatergic excitatory transmission in adult rat substantia gelatinosa neurons. J. Neurophysiol. 102, 312–319.

    Article  PubMed  CAS  Google Scholar 

  21. Fong S.W., McLennan I.S., McIntyre A., Reid J., Shennan K.I.J., Bewick G.S. 2010. TGF-beta2 alters the characteristics of the neuromuscular junction by regulating presynaptic quantal size. Proc. Natl. Acad. Sci. USA. 107, 13515–13519.

    Article  PubMed  Google Scholar 

  22. Faraut B., Barbier J., Ravel-Chapuis A., Doyennette M.-A., Jandrot-Perrus M., Verdière-Sahuqué M., Schaeffer L., Koenig J., Hantaï D. 2003. Thrombin downregulates muscle acetylcholine receptors via an IP3 signaling pathway by activating its G-protein-coupled protease-activated receptor-1. J. Cell. Physiol. 196, 105–112.

    Article  PubMed  CAS  Google Scholar 

  23. Hoffmann C., Weigert C. 2017. Skeletal muscle as an endocrine organ: The role of myokines in exercise adaptations. Cold Spring Harb. Perspect. Med. a029793.

    Google Scholar 

  24. Pitts E.V., Potluri S., Hess D.M., Balice-Gordon R. J. 2006. Neurotrophin and Trk-mediated signaling in the neuromuscular system. Int. Anesthesiol. Clin. 44, 21–76.

    Article  PubMed  Google Scholar 

  25. Hurtado E., Cilleros V., Nadal L., Simó A., Obis T., Garcia N., Santafé M.M., Tomàs M., Halievski K., Jordan C.L., Lanuza M.A., Tomàs J. 2017. Muscle contraction regulates BDNF/TrkB signaling to modulate synaptic function through presynaptic cPKCα and cPKCβI. Front. Mol. Neurosci. 10, 147.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Garcia N., Tomàs M., Santafé M.M., Besalduch N., Lanuza M.A., Tomàs J. 2010. The interaction between tropomyosin-related kinase B receptors and presynaptic muscarinic receptors modulates transmitter release in adult rodent motor nerve terminals. J. Neurosci. 30, 16514–16522.

    Article  PubMed  CAS  Google Scholar 

  27. Gaydukov A.E., Balezina O.P. 2006. Potentiating effect of allatostatin on transmitter quantal secretion in the mouse nerve-muscle synapse. J. Evol. Biochem. Physiol. 42, 699–705.

    Article  CAS  Google Scholar 

  28. Garcia N., Tomàs M., Santafe M.M., Lanuza M.A., Besalduch N., Tomàs, J. 2010. Localization of brainderived neurotrophic factor, neurotrophin-4, tropomyosin-related kinase b receptor, and p75 NTR receptor by high-resolution immunohistochemistry on the adult mouse neuromuscular junction. J. Peripher. Nerv. Syst. 15, 40–49.

    Article  PubMed  CAS  Google Scholar 

  29. Santafé M.M., Garcia N., Tomàs M., Obis T., Lanuza M.A., Besalduch N., Tomàs J. 2014. The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions. Neurosci. Lett. 561, 171–175.

    Article  PubMed  CAS  Google Scholar 

  30. Fujimura H., Altar C.A., Chen R., Nakamura T., Nakahashi T., Kambayashi J., Sun B., Tandon N.N. 2002. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb. Haemost. 87, 728–734.

    Article  PubMed  CAS  Google Scholar 

  31. Tamura S., Suzuki H., Hirowatari Y., Hatase M., Nagasawa A., Matsuno K., Kobayashi S., Moriyama T. 2011. Release reaction of brain-derived neurotrophic factor (BDNF) through PAR1 activation and its two distinct pools in human platelets. Thromb. Res. 128, e55–e61.

    Article  PubMed  CAS  Google Scholar 

  32. Boulanger L.M., Poo M.M. 1999. Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation. Nat. Neurosci. 2, 346–351.

    Article  PubMed  CAS  Google Scholar 

  33. Tyler W.J., Perrett S.P., Pozzo-Miller L.D. 2002. The role of neurotrophins in neurotransmitter release. Neurosci. 8, 524–531.

    CAS  Google Scholar 

  34. Pousinha P.A., Diogenes M.J., Ribeiro J.A., Sebastião A.M. 2006. Triggering of BDNF facilitatory action on neuromuscular transmission by adenosine A2A receptors. Neurosci. Lett. 404, 143–147.

    Article  PubMed  CAS  Google Scholar 

  35. Santi S., Cappello S., Riccio M., Bergami M., Aicardi G., Schenk U., Matteoli M., Canossa M. 2006. Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance. EMBO J. 25, 4372–4380.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Cheng Q., Song S.-H., Augustine G.J. 2017. Calciumdependent and synapsin-dependent pathways for the presynaptic actions of BDNF. Front. Cell. Neurosci. 11, 75.

    PubMed  PubMed Central  Google Scholar 

  37. Yang F., Je H.-S., Ji Y., Nagappan G., Hempstead B., Lu B. 2009. Pro-BDNF-induced synaptic depression and retraction at developing neuromuscular synapses. J. Cell Biol. 185, 727–741.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Mbebi C., Rohn T., Doyennette M.A., Chevessier F., Jandrot-Perrus M., Hantaï D., Verdière-Sahuqué M. 2001. Thrombin receptor induction by injury-related factors in human skeletal muscle cells. Exp. Cell Res. 263, 77–87.

    Article  PubMed  CAS  Google Scholar 

  39. Chowdhury M.H., Nagai A., Terashima M., Sheikh A., Murakawa Y., Kobayashi S., Yamaguchi S. 2008. Chemokine-like factor expression in the idiopathic inflammatory myopathies. Acta Neurol. Scand. 118, 106–114.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biology Department, Moscow Lomonosov State University, Moscow, 119234, Russia

    A. E. Gaydukov, I. A. Akutin, P. O. Bogacheva & O. P. Balezina

Authors
  1. A. E. Gaydukov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. A. Akutin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. O. Bogacheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O. P. Balezina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. E. Gaydukov.

Additional information

Original Russian Text © A.E. Gaydukov, I.A. Akutin, P.O. Bogacheva, O.P. Balezina, 2017, published in Biologicheskie Membrany, 2017, Vol. 34, No. 5, pp. 30–41.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaydukov, A.E., Akutin, I.A., Bogacheva, P.O. et al. Changes in the Parameters of Quantal Acetylcholine Release after Activation of PAR1-Type Thrombin Receptors at the Mouse Neuromuscular Junctions. Biochem. Moscow Suppl. Ser. A 12, 33–42 (2018). https://doi.org/10.1134/S1990747818010063

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990747818010063

Keywords

Search

Navigation