End‐plate voltage‐gated sodium channels are lost in clinical and experimental myasthenia gravis

Abstract

This study examined the loss of voltage-gated Na+ channels as well as acetylcholine receptors (AChRs) from the end-plate region in patients with acquired myasthenia gravis (MG) and in rats with experimental autoimmune passively transferred MG (PTMG). Rats received a monoclonal IgG antibody directed against an extracellular epitope of the nicotinic acetylcholine receptor of muscle (AChR) to produce PTMG. At the end-plate border we examined miniature end-plate potentials (MEPPs), sodium current (INa) amplitude, and action potential (AP) properties; the latter two were also examined on the extrajunctional membrane. In the normal situation, the safety factor for neuromuscular transmission is ensured by the large INa at the end plate, which reduces the AP threshold. Among different fiber types, INa was largest for type IIb fibers and smallest for type I fibers. When end-plate border properties of fibers from 3 MG patients and 15 PTMG rats were compared with controls, INa was reduced, AP thresholds were higher, and rates of AP rise were reduced. Amplitudes of MEPPs and INa at the end plate indicated that loss of AChRs was greater than loss of Na+ channels in patients with MG and rats with PTMG; INa was reduced to about 60% of control values, whereas MEPPs were reduced to less than 30% of control values. On the extrajunctional membrane, INa and AP thresholds and rates of rise were similar for MG patients, PTMG rats, and controls. This evidence for loss of voltage-gated Na+ channels at the motor end plate in both patients with MG and in rats with PTMG reveals a hitherto unrecognized consequence of the end-plate damage initiated by the binding of complement-fixing IgG to end-plate AChRs.

Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding

“…Therefore, it can be argued that increased postsynaptic folding in rapsyn-silenced muscles may serve to compensate for the loss of rapsyn-AChR clusters at the postsynaptic membrane, which would otherwise lead to a great reduction of the safety factor, as we presently observed in EAMG muscle. This is in line with previous observations that the complexity of postsynaptic folding of the neuromuscular junction can increase the safety factor (Ruff and Lennon, 1998;Slater, 1997, 2001). In this respect, it is interesting to note that the human neuromuscular junction has used the same strategy to compensate for low AChR expression compared to other species, which in turn have less complex postsynaptic folding (Wood and Slater, 2001).…”

Autoimmune disorders of the neuromuscular junction

“…This could be important as the voltage-gated sodium channels responsible for initiating the action potential are located at the bottom of the folds. [39] Several factors could modify the degree of AChR loss and thereby disease severity. Complement regulatory proteins are present which probably reduce the damage caused by complement-activating antibodies [40] and as mentioned above there is increased AChR synthesis.…”

Measurement of contractile force of skeletal and extraocular muscles: Effects of blood supply, muscle size and in situ or in vitro preparation

“…The firing rates of extraocular muscle myofibers are higher than those of limb myofibers, which places an additional electrical stress on the extraocular muscle synapses. The increased electrical stress results in a greater influence on sodium channel inactivation, AChR desensitization, and affects the efficiency of neuromuscular transmission (Ruff and Lennon, 1998;Ruff, 2002). Thus, the benefit of a relatively large nerve terminal and endplate size of en plaque fibers of extraocular muscle may be that it increases the safety factor for neuromuscular transmission and provides protection for the neuromuscular junction in ischemic conditions.…”