Lambert–Eaton myasthenic syndrome: Search for alternative autoimmune targets and possible compensatory mechanisms based on presynaptic calcium homeostasis
Section snippets
Voltage-gated calcium channels
As Professor Newsom-Davis stated in his posthumous review (Newsom-Davis, 2007), “Research advances over 30 years have shown that key transmembrane proteins at the neuromuscular junction are vulnerable to antibody-mediated autoimmune attack”. One example is the voltage-gated calcium channel (VGCC) in the Lambert–Eaton myasthenic syndrome (LEMS). The story of research on LEMS began in 1953, when Anderson et al. (1953) first reported a 47-year-old man with lung carcinoma who showed prolonged apnea
Synaptotagmin
Since the discovery that calcium entry into nerve terminals triggers rapid neurotransmitter release, the search for calcium sensors has intensified. It is now generally agreed that the synaptic vesicle-associated calcium binding protein, synaptotagmin, is required for the tight temporal coupling between calcium influx and synaptic vesicle exocytosis, which is due to intimate apposition between the phospholipid membrane and the SNARE complex (synaptobrevin, syntaxin and SNAP-25), followed by
Presynaptic muscarinic acetylcholine receptor
In the Symposium on myasthenia gravis and myasthenic syndrome in the 8th International Congress of Neuroimmunology held in 2006 (at Nagoya), Professor Newsom-Davis encouraged our further searches for LEMS targets other than P/Q-type VGCC. We tested LEMS sera for antibodies against likely target antigens and compensatory mediators for the defective neuromuscular transmission in LEMS, focusing particularly on the M1-type presynaptic muscarinic acetylcholine receptor (M1 mAChR), a G
Compensatory mechanisms
Besides the M1 mAChR-related signaling we propose, the Oxford group has suggested that potential presynaptic mechanisms that compensate for the immune-mediated defect of calcium entry in LEMS could include a shift in dependence of ACh release from the P/Q-type to other types of VGCC such as L-, N-, and/or R-types (Giovannini et al., 2002, Lang et al., 2003). In addition, a switch from slow- to fast-mode synaptic vesicle recycling (“kiss-and-run”) might also contribute; this clathrin-independent
Acknowledgments
We dedicate this paper with sincere gratitude to Professor Newsom-Davis who lit beacons for our ongoing research. We gratefully acknowledge the helpful contributions from the Oxford research group to the preparation of the manuscript.
References (63)
- et al.
Bronchial neoplasm with myasthenia. Prolonged apnea after administration of succinylcholine
Lancet
(1953) - et al.
Presynaptic neuronal antigens expressed by a small cell lung carcinoma cell line
J. Neuroimmunol.
(2001) - et al.
A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter
J. Biol. Chem.
(2007) - et al.
Expression of synaptotagmin and syntaxin associated with N-type calcium channels in small cell lung cancer
FEBS Lett.
(1993) - et al.
Mechanisms underlying the rapid induction and sustained expression of synaptic homeostasis
Neuron
(2006) - et al.
Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multi-protein complex centered on TRPC6 channels
J. Biol. Chem.
(2005) - et al.
Calcium channel peptide can cause an autoimmune-mediated model of Lambert–Eaton myasthenic syndrome in rats
J. Neurol. Sci.
(1999) - et al.
Favourable prognosis in Lambert–Eaton myasthenic syndrome and small-cell lung carcinoma
Lancet
(1999) - et al.
Coupling of presynaptic muscarinic autoreceptors to serine kinases in low and high release conditions on the rat motor nerve terminal
Neuroscience
(2007) - et al.
Alpha-neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction
Neuroscience
(2006)