nPKCε Mediates SNAP-25 Phosphorylation of Ser-187 in Basal Conditions and After Synaptic Activity at the Neuromuscular Junction

  • Anna Simó
  • Victor Cilleros-Mañé
  • Laia Just-Borràs
  • Erica Hurtado
  • Laura Nadal
  • Marta Tomàs
  • Neus Garcia
  • Maria A. LanuzaEmail author
  • Josep TomàsEmail author


Protein kinase C (PKC) and substrates like SNAP-25 regulate neurotransmission. At the neuromuscular junction (NMJ), PKC promotes neurotransmitter release during synaptic activity. Thirty minutes of muscle contraction enhances presynaptic PKC isoform levels, specifically cPKCβI and nPKCε, through retrograde BDNF/TrkB signaling. This establishes a larger pool of these PKC isoforms ready to promote neuromuscular transmission. The PKC phosphorylation site in SNAP-25 has been mapped to the serine 187 (Ser-187), which is known to enhance calcium-dependent neurotransmitter release in vitro. Here, we localize SNAP-25 at the NMJ and investigate whether cPKCβI and/or nPKCε regulate SNAP-25 phosphorylation. We also investigate whether nerve and muscle cell activities regulate differently SNAP-25 phosphorylation and the involvement of BDNF/TrkB signaling. Our results demonstrate that nPKCε isoform is essential to positively regulate SNAP-25 phosphorylation on Ser-187 and that muscle contraction prevents it. TrkB and cPKCβI do not regulate SNAP-25 protein level or its phosphorylation during neuromuscular activity. The results provide evidence that nerve terminals need both pre- and postsynaptic activities to modulate SNAP-25 phosphorylation and ensure an accurate neurotransmission process.


Neuromuscular junction Muscle contraction SNAP-25 TrkB PKC Neurotransmission Synaptic vesicles 



Anti-TrkB antibody clone 47/TrkB




Acetylcholine receptor


Brain-derived neurotrophic factor


Calcium ion


Central nervous system


Conventional protein kinase C beta I


Enhanced chemiluminescence


Glyceraldehyde-3-phosphate dehydrogenase


Horseradish peroxidase


Levator auris longus


Neuromuscular junction


Novel protein kinase C epsilon




p75 neurotrophin receptor


Phosphate buffer saline


Protein kinase C


Phospholipase C


Phorbol 12-myristate 13-acetate


Phosphorylated synaptosomal-associated protein of 25 kDa


Polyvinylidene difluoride


Receptor for activated C-kinase


Sodium dodecyl sulfate


Serine 187


Synaptosomal-associated protein of 25 kDa


Soluble N-ethylmaleimide-sensitive factor attachment receptor proteins


Tropomyosin receptor kinase A


Tropomyosin receptor kinase B


Tropomyosin receptor kinase C




cPKCβI-specific translocation inhibitor peptide


nPKCε-specific translocation inhibitor peptide


μ-Conotoxin GIIIB


Voltage-gated calcium channels



We would like to thank Dr. Daria Mochly-Rosen and Dr. Nir Qvit for providing the specific translocation inhibitor peptide of cPKCβI (βIV5-3).

Authors’ Contributions

A.S.: data collection, quantitative analysis, literature search, data interpretation, statistics; V.C., L.J.: data collection, quantitative analyses, literature search, data interpretation, design graphic abstract; E.H., L.N., and M.T.: data interpretation; J.T., M.A.L, and N.G.: conception and design, literature search, data interpretation, manuscript preparation

Funding Information

This work has been possible with the support of the Ministerio de Economía, Industria y Competitividad (MINECO), the Agencia Estatal de Investigación (AEI), the European Regional Development Fund (ERDF) (SAF2015-67143-P), the Universitat Rovira i Virgili (URV) (2014PFR-URV-B2-83 and 2017PFR-URV-B2-85), and the Catalan Government (2014SGR344 and 2017SGR704). V.C. has been supported by MINECO under the framework of the Sistema Nacional de Garantía Juvenil, the European Social Fund (ESF), and the Iniciativa de Empleo Juvenil (IEJ).

Compliance with Ethical Standards

Young adult Sprague-Dawley rats (30–40 days; Criffa, Barcelona, Spain; RRID:RGD_5508397) were cared for in accordance with the guidelines of the European Community Council Directive for the humane treatment of laboratory animals. All the procedures were approved by the Animal Experimentation Ethics Committee of the Universitat Rovira i Virgili.

Competing Interests

The authors declare that they have no competing interests.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la SalutUniversitat Rovira i VirgiliReusSpain

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