[Recent advance in research for myasthenia gravis, in relation to various antibodies affecting synaptic structure and function].
Autoantibodies impair acetylcholine receptor (AChR) in myasthenia gravis (MG) and P/Q-type voltage-gated calcium channel (VGCC) in Lambert-Eaton myasthenic syndrome (LEMS). (1) Some of MG and LEMS patients are "seronegative" for respective antibodies or modified by antibodies that recognize other proteins than AChR and VGCC such as MuSK, AChR allosteric site, membrane Na+ channel and ryanodine receptor-1 (RyR1) in MG, and synaptotagmin-1 in LEMS. (2) Autoimmune responses affect the proteins participating in the mechanisms to compensate for synaptic disorders on the basis of presynaptic Ca2+ homeostasis provided by VGCC and non-VGCC (receptor-operated TRPCs): they act as enhancers of Ca(2+) -mediated ACh release via phospholipase C signaling pathways including M1-type presynaptic muscarinic AChR, neurotrophin receptor (TrkB), and fast-mode of synaptic vesicle recycling. (3) The pathophysiology contributive to contractile fatigue in MG includes RyR1 and also TRPC3. The TRPC3 also forms a complex with STIM1 and Orail to make up for Ca2+ after sarcoplasmic Ca2+ release. The prevalent detection of anti-TRPC3 antibodies in MG with thymoma could affect muscle contractile machineries in addition to anti-RyR1-induced affection. (4) When one faces "seronegative" MG, one should be cautious to conformation-specific antibodies and also congenital myasthenic syndromes.
Takamori
Masaharu
M
Neurological Center, Kanazawa-Nishi Hospital.
D001323:Autoantibodies; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D015220:Calcium Channels / Q000276:immunology; D020013:Calcium Signaling / Q000502:physiology; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome / Q000235:genetics / Q000276:immunology; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology; D011976:Receptors, Muscarinic / Q000276:immunology; D011978:Receptors, Nicotinic / Q000276:immunology; D019837:Ryanodine Receptor Calcium Release Channel / Q000276:immunology; D013569:Synapses / Q000276:immunology* / Q000502:physiology; D050863:Synaptotagmin I / Q000276:immunology; D050052:TRPC Cation Channels / Q000276:immunology
D001323:Autoantibodies; D015220:Calcium Channels; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D019837:Ryanodine Receptor Calcium Release Channel; D050863:Synaptotagmin I; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D002118:Calcium