title: 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.
authors.affiliation: Neurology Service, Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Ruff
authors.forename: V A
authors.initials: VA
authors.lastname: Lennon
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000328:Adult; D000818:Animals; D017364:Collagenases / Q000494:pharmacology; D004056:Differential Threshold / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D009045:Motor Endplate / Q000502:physiology*; D009157:Myasthenia Gravis / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D015222:Sodium Channels / Q000502:physiology*
chemical_list: D015222:Sodium Channels; D017364:Collagenases