K. Jahn et al., Mechanism of block of nicotinic acetylcholine receptor channels by purified IgG from seropositive patients with myasthenia gravis, NEUROLOGY, 54(2), 2000, pp. 474-479
Objective: To clarify the mechanism of block of nicotinic receptor channels
by myasthenic antibodies. Background: Nicotinic acetylcholine receptor (nA
ChR) channel currents are functionally blocked by purified immunoglobulin G
(IgG) of patients with myasthenia gravis (MG). Methods: The molecular mech
anism of block of IgG fractions containing antibodies to nAChR channels was
tested with the patch-clamp technique in combination with a system for ult
rafast solution exchange. For the experiments, outside-out patches from cul
tured mouse myotubes that express embryonic-type nAChR channels at their su
rface were used. Results: Incubation of outside-out patches with purified I
gG from four myasthenic patients blocked nAChR channel currents activated b
y the application of 1.0 mM ACh reversibly. The peak current amplitude and
the time course of block of nAChR channels decreased with increasing concen
trations of IgG. The block became at least partly irreversible if incubatio
n time of outside-out patches exceeded 2 minutes. For the block of nAChR ch
annel currents with alpha-bungarotoxin, a similar mechanism of block was fo
und. Conclusions: The reversibility of functional block of nAChR channel cu
rrents by myasthenic IgG depended strongly on the incubation time of the re
ceptors with antibodies. Interaction of myasthenic antibodies with nicotini
c receptors may proceed in several stages from a low-affinity reversible to
a high-affinity irreversible binding. Key words: Myasthenia gravis-Block m
echanism-Myasthenic antibodies-Immunoglobulin G-Patch-clamp technique-Ultra
fast application-Nicotinic acetylcholine receptor.