The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions

2014 ◽  
Vol 561 ◽  
pp. 171-175 ◽  
Author(s):  
Manel M. Santafé ◽  
Neus Garcia ◽  
Marta Tomàs ◽  
Teresa Obis ◽  
Maria A. Lanuza ◽  
...  
Keyword(s):  
Acetylcholine Release ◽  
Neuromuscular Junctions ◽  
Serine Kinases ◽  
Tropomyosin Related Kinase B

scholarly journals Inhibition of Kv2.1 Potassium Channels by MiDCA1, A Pre-Synaptically Active PLA2-Type Toxin from Micrurus dumerilii carinicauda Coral Snake Venom

Toxins ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 335
Author(s):  
Niklas Schütter ◽  
Yuri Correia Barreto ◽  
Vitya Vardanyan ◽  
Sönke Hornig ◽  
Stephen Hyslop ◽  
...  
Keyword(s):  
Snake Venom ◽  
Potassium Current ◽  
Acetylcholine Release ◽  
Channel Blocker ◽  
Neuromuscular Junctions ◽  
Coral Snake ◽  
Drg Neurons ◽  
Kv Channels ◽  
Heterologous System ◽  
Outward Potassium Current

MiDCA1, a phospholipase A2 (PLA2) neurotoxin isolated from Micrurus dumerilii carinicauda coral snake venom, inhibited a major component of voltage-activated potassium (Kv) currents (41 ± 3% inhibition with 1 μM toxin) in mouse cultured dorsal root ganglion (DRG) neurons. In addition, the selective Kv2.1 channel blocker guangxitoxin (GxTx-1E) and MiDCA1 competitively inhibited the outward potassium current in DRG neurons. MiDCA1 (1 µM) reversibly inhibited the Kv2.1 current by 55 ± 8.9% in a Xenopus oocyte heterologous system. The toxin showed selectivity for Kv2.1 channels over all the other Kv channels tested in this study. We propose that Kv2.1 channel blockade by MiDCA1 underlies the toxin’s action on acetylcholine release at mammalian neuromuscular junctions.

Spontaneous acetylcholine release in mammalian neuromuscular junctions

1997 ◽  
Vol 273 (6) ◽  
pp. C1835-C1841 ◽  
Author(s):  
Adriana Losavio ◽  
S. Muchnik
Keyword(s):  
Neuromuscular Junction ◽  
Acetylcholine Release ◽  
Neuromuscular Junctions ◽  
The Other ◽  
Nerve Terminals ◽  
Transmitter Secretion ◽  
Other Hand ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Lower Effect

Spontaneous secretion of the neurotransmitter acetylcholine in mammalian neuromuscular synapsis depends on the Ca2+ content of nerve terminals. The Ca2+ electrochemical gradient favors the entry of this cation. We investigated the possible involvement of three voltage-dependent Ca2+ channels (VDCC) (L-, N-, and P/Q-types) on spontaneous transmitter release at the rat neuromuscular junction. Miniature end-plate potential (MEPP) frequency was clearly reduced by 5 μM nifedipine, a blocker of the L-type VDCC, and to a lesser extent by the N-type VDCC blocker, ω-conotoxin GVIA (ω-CgTx, 5 μM). On the other hand, nifedipine and ω-CgTx had no effect on K+-induced transmitter secretion. ω-Agatoxin IVA (100 nM), a P/Q-type VDCC blocker, prevents acetylcholine release induced by K+ depolarization but failed to affect MEPP frequency in basal conditions. These results suggest that in the mammalian neuromuscular junction Ca2+ enters nerve terminals through at least three different channels, two of them (L- and N-types) mainly related to spontaneous acetylcholine release and the other (P/Q-type) mostly involved in depolarization-induced neurotransmitter release. Ca2+-binding molecule-related spontaneous release apparently binds Ca2+ very rapidly and would probably be located very close to Ca2+ channels, since the fast Ca2+ chelator (BAPTA-AM) significantly reduced MEPP frequency, whereas EGTA-AM, exhibiting slower kinetics, had a lower effect. The increase in MEPP frequency induced by exposing the preparation to hypertonic solutions was affected by neither external Ca2+concentration nor L-, N-, and P/Q-type VDCC blockers, indicating that extracellular Ca2+ is not necessary to produce hyperosmotic neurosecretion. On the other hand, MEPP frequency was diminished by BAPTA-AM and EGTA-AM to the same extent, supporting the view that hypertonic response is promoted by “bulk” intracellular Ca2+concentration increases.

scholarly journals Regulation of Acetylcholine Quantal Release by Coupled Thrombin/BDNF Signaling in Mouse Motor Synapses

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 762 ◽  
Author(s):  
Alexander Gaydukov ◽  
Polina Bogacheva ◽  
Ekaterina Tarasova ◽  
Anastasia Molchanova ◽  
Anna Miteva ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Neuromuscular Junctions ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Functional Coupling ◽  
A2a Receptors ◽  
A2a Adenosine Receptors ◽  
Quantal Size ◽  
Tropomyosin Related Kinase B ◽  
Endplate Potentials

The aim of this study was to compare the acute effects of thrombin and brain-derived neurotrophic factor (BDNF) on spontaneous miniature endplate potentials (MEPPs) and multiquantal evoked endplate potentials (EPPs) in mouse neuromuscular junctions (NMJs) of m. diaphragma and m. EDL. Intracellular microelectrode recordings of MEPPs and EPPs were used to evaluate the changes in acetylcholine (ACh) release in mature and newly-formed mouse NMJs. Thrombin (1 nM) increased the amplitude of MEPPs and EPPs by 25–30% in mature and newly-formed NMJs. This effect was due to an enhanced loading of synaptic vesicles with ACh and increase of ACh quantal size, since it was fully prevented by blocking of vesicular ACh transporter. It was also prevented by tropomyosin-related kinase B (TrkB) receptors inhibitor ANA12. Exogenous BDNF (1 nM) mimicked thrombin effect and increased the amplitude of MEPPs and EPPs by 25–30%. It required involvement of protein kinase A (PKA) and mitogen-activated protein kinase (MEK1/2)-mediated pathway, but not phospholipase C (PLC). Blocking A2A adenosine receptors by ZM241385 abolished the effect of BDNF, whereas additional stimulation of A2A receptors by CGS21680 increased MEPP amplitudes, which was prevented by MEK1/2 inhibitor U0126. At mature NMJs, BDNF enhanced MEPPs frequency by 30–40%. This effect was selectively prevented by inhibition of PLC, but not PKA or MEK1/2. It is suggested that interrelated effects of thrombin/BDNF in mature and newly-formed NMJs are realized via enhancement of vesicular ACh transport and quantal size increase. BDNF-induced potentiation of synaptic transmission involves the functional coupling between A2A receptor-dependent active PKA and neurotrophin-triggered MAPK pathway, as well as PLC-dependent increase in frequency of MEPPs.

scholarly journals Staurosporine inhibits agrin-induced acetylcholine receptor phosphorylation and aggregation.

1994 ◽  
Vol 125 (3) ◽  
pp. 661-668 ◽  
Author(s):  
B G Wallace
Keyword(s):  
Tyrosine Phosphorylation ◽  
Acetylcholine Receptor ◽  
Tyrosine Kinases ◽  
Neuromuscular Junctions ◽  
Beta Subunit ◽  
Dependent Manner ◽  
Tyrosine Residues ◽  
Serine Kinases ◽  
Cultured Myotubes ◽  
Dose Dependent

Agrin, a protein that mediates nerve-induced acetylcholine receptor (AChR) aggregation at developing neuromuscular junctions, has been shown to cause an increase in phosphorylation of the beta, gamma, and delta subunits of AChRs in cultured myotubes. As a step toward understanding the mechanism of agrin-induced AChR aggregation, we examined the effects of inhibitors of protein kinases on AChR aggregation and phosphorylation in chick myotubes in culture. Staurosporine, an antagonist of both protein serine and tyrosine kinases, blocked agrin-induced AChR aggregation in a dose-dependent manner; 50% inhibition occurred at approximately 2 nM. The extent of inhibition was independent of agrin concentration, suggesting an effect downstream of the interaction of agrin with its receptor. Staurosporine blocked agrin-induced phosphorylation of the AChR beta subunit, which occurs at least in part on tyrosine residues, but did not reduce phosphorylation of the gamma and delta subunits, which occurs on serine/threonine residues. Staurosporine also prevented the agrin-induced decrease in the rate at which AChRs are extracted from intact myotubes by mild detergents. H-7, an antagonist of protein serine kinases, inhibited agrin-induced phosphorylation of the gamma and delta subunits but did not block agrin-induced phosphorylation of the AChR beta subunit, AChR aggregation, or the decrease in AChR extractability. The results provide support for the hypothesis that tyrosine phosphorylation of the beta subunit plays a role in agrin-induced AChR aggregation.

scholarly journals Adrenoceptors Modulate Cholinergic Synaptic Transmission at the Neuromuscular Junction

2021 ◽  
Vol 22 (9) ◽  
pp. 4611
Author(s):  
Ellya Bukharaeva ◽  
Venera Khuzakhmetova ◽  
Svetlana Dmitrieva ◽  
Andrei Tsentsevitsky
Keyword(s):  
Neuromuscular Junction ◽  
Neurodegenerative Diseases ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Acetylcholine Release ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Nerve Terminals ◽  
Adrenergic Agents ◽  
Cholinergic Synaptic Transmission

Adrenoceptor activators and blockers are widely used clinically for the treatment of cardiovascular and pulmonary disorders. More recently, adrenergic agents have also been used to treat neurodegenerative diseases. Recent studies indicate a location of sympathetic varicosities in close proximity to neuromuscular junctions. The pressing question is whether there could be any effects of endo- or exogenous catecholamines on cholinergic neuromuscular transmission. It was shown that the pharmacological stimulation of adrenoceptors, as well as sympathectomy, can affect both acetylcholine release from motor nerve terminals and the functioning of postsynaptic acetylcholine receptors. In this review, we discuss the recent data regarding the effects of adrenergic drugs on neurotransmission at the neuromuscular junction. The elucidation of the molecular mechanisms by which the clinically relevant adrenomimetics and adrenoblockers regulate quantal acetylcholine release from the presynaptic nerve terminals and postsynaptic sensitivity may help in the design of highly effective and well-tolerated sympathomimetics for treating a number of neurodegenerative diseases accompanied by synaptic defects.

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