• Acetylcholine;
  • autoimmune;
  • Lambert-Eaton myasthenic syndrome;
  • neuromuscular junction;
  • voltage-dependent calcium channels
  • Acetylcholine release at the neuromuscular junction relies on rapid, local and transient calcium increase at presynaptic active zones, triggered by the ion influx through voltage-dependent calcium channels (VDCCs) clustered on the presynaptic membrane. Pharmacological investigation of the role of different VDCC subtypes (L-, N-, P/Q- and R-type) in spontaneous and evoked acetylcholine (ACh) release was carried out in adult mouse neuromuscular junctions (NMJs) under normal and pathological conditions.

  • ω-Agatoxin IVA (500 nM), a specific P/Q-type VDCC blocker, abolished end plate potentials (EPPs) in normal NMJs. However, when neurotransmitter release was potentiated by the presence of the K+ channel blocker 4-aminopyridine (4-AP), an ω-agatoxin IVA- and ω-conotoxin MVIIC-resistant component was detected. This resistant component was only partially sensitive to 1 μM ω-conotoxin GVIA (N-type VDCC blocker), but insensitive to any other known VDCC blockers. Spontaneous release was dependent only on P/Q-type VDCC in normal NMJs. However, in the presence of 4-AP, it relied on L-type VDCCs too.

  • ACh release from normal NMJs was compared with that of NMJs of mice passively injected with IgGs obtained from patients with Lambert-Eaton myasthenic syndrome (LEMS), a disorder characterized by a compromised neurotransmitter release. Differently from normal NMJs, in LEMS IgGs-treated NMJs an ω-agatoxin IVA-resistant EPP component was detected, which was only partially blocked by calciseptine (1 μM), a specific L-type VDCC blocker.

  • Altogether, these data demonstrate that multiple VDCC subtypes are present at the mouse NMJ and that a resistant component can be identified under ‘pharmacological’ and/or ‘pathological’ conditions.

British Journal of Pharmacology (2002) 136, 1135–1145. doi:10.1038/sj.bjp.0704818