Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders.
The Lambert-Eaton myasthenic syndrome (LEMS), often associated with small-cell lung carcinoma (SCLC), is a disorder of acetylcholine (ACh) release from motor nerve terminals. In most patients, it is caused by autoantibodies against the P/Q-type voltage-gated calcium channels (VGCC) that trigger ACh release. However, these antibodies are not detected in approximately 15% of clinically and electrophysiologically typical cases. The M1-type pre-synaptic muscarinic ACh receptor (M1 mAChR) modulates cholinergic neuromuscular transmission by linking to P/Q-type VGCC, and may partially compensate for the reduced calcium entry. Immunoblotting against solubilized human M1 mAChR, we detected autoantibodies in: (a) 14 of 20 (70%) anti-VGCC-positive LEMS patients; (b) all five anti-VGCC-negative LEMS patients, one of whose serum had previously passively transferred LEMS-type electrophysiological defects to mice; (c) all five LEMS patients with autonomic symptoms; (d) seven of 25 (28%) myasthenia gravis (MG) patients in whom increased ACh release partially compensates for post-synaptic defects; (e) none of 10 SCLC patients without LEMS. Although not proving primary pathogenicity of anti-M1 mAChR antibodies, the present results highlight their potential to affect synaptic compensatory mechanisms, more in LEMS than MG.
Takamori
M
M
Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Japan. t-kiyomi@guitar.ocn.ne.jp
Motomura
M
M
Fukudome
T
T
Yoshikawa
H
H
D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D043643:Receptor, Muscarinic M1 / Q000276:immunology*
D001323:Autoantibodies; D043643:Receptor, Muscarinic M1