Premium
Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions
Author(s) -
Giovannini F,
Sher E,
Webster R,
Boot J,
Lang B
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704818
Subject(s) - neuromuscular junction , acetylcholine , neurotransmitter , voltage dependent calcium channel , 4 aminopyridine , congenital myasthenic syndrome , chemistry , conotoxin , neuromuscular transmission , calcium channel , calcium , acetylcholine receptor , pharmacology , neuroscience , biophysics , endocrinology , biology , venom , biochemistry , potassium channel , receptor , organic chemistry
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 n M ), 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 μ M 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 μ M ), 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