Passive transfer of Lambert-Eaton syndrome to mice induces dihydropyridine sensitivity of neuromuscular transmission.
Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic disorder in which autoantibodies apparently target the voltage-gated Ca2+ channels that regulate acetylcholine (ACh) release at motor nerve terminals. P/Q-type Ca2+ channels are primarily involved in ACh release at mammalian neuromuscular junctions. Passive transfer of LEMS to mice by repeated administration of plasma from LEMS patients reduces the amplitude of the perineurial P/Q-type current, and unmasks a dihydropyridine (DHP)-sensitive L-type Ca2+ current at the motor nerve terminal. The present study sought to determine if this DHP-sensitive component contributes to ACh release. Mice were treated for 30 days with plasma from healthy human controls or patients with LEMS. For some studies, diaphragms from naive mice were incubated with LEMS or control human plasma for 2 or 24 h. End-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) were recorded from neuromuscular junctions in the hemidiaphragm. Treatment of mice with LEMS plasma evoked the characteristic electrophysiological signs of LEMS: reduced quantal content and facilitation of EPP amplitudes at high-frequency stimulation. Quantal content was also reduced in muscles incubated acutely with LEMS plasma. Nimodipine, a DHP-type blocker of L-type Ca2+ channels, did not significantly affect the quantal content of muscles treated for 2 or 24 h with either control or LEMS plasma, or following chronic treatment with control plasma. However, following 30 days treatment with LEMS plasma, nimodipine significantly reduced the remaining quantal content to 57.7 +/- 3.3 % of pre-nimodipine control levels. Thus, DHP-sensitive Ca2+ channels become involved in synaptic transmission at the mouse neuromuscular junction after chronic, but not acute treatment with LEMS plasma. However, reductions in quantal release of ACh occur even after very short periods of exposure to LEMS plasma. As such, development of the L-type Ca2+ channel contribution to ACh release during passive transfer of LEMS appears to occur only after quantal release is significantly impaired for an extended duration, suggesting that an adaptive response of the ACh release apparatus occurs in LEMS.
Flink
Michael T
MT
Department of Pharmacology and Toxicology, Michigan State University, B-331 Life Sciences Building, East Lansing, MI 48824-1317, USA.
Atchison
William D
WD
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000276:immunology / Q000378:metabolism; D003964:Diaphragm / Q000294:innervation / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D007116:Immunization, Passive; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D000109:Acetylcholine