Reduction of Calcium Currents by Lambert–Eaton Syndrome Sera: Motoneurons Are Preferentially Affected, and L-Type Currents Are Spared

Abstract

Previous work has demonstrated that Lambert-Eaton syndrome (LES) antibodies reduce calcium currents in nonneuronal cells and sensory neurons and reduce the amplitude of extracellularly recorded currents at mouse motor nerve terminals. We compared effects of LES sera on whole-cell currents of cultured nerve and muscle. LES sera more strongly reduced calcium currents in motoneurons than in sensory neurons. Motoneuronal potassium currents were unaffected. The sera minimally affected calcium currents in skeletal and cardiac muscle. In motoneurons, both low voltage-activated (LVA) and high voltage-activated (HVA) components of calcium current were decreased, demonstrating that the sera targeted more than one calcium channel type. The HVA current remaining in LES-treated motoneurons was little affected by micromolar -conotoxin MVIIC but was reduced Ͼ70% by micromolar nimodipine. This pharmacological profile contrasts with untreated cells and suggests that LES sera primarily spare L-type currents in motoneurons.

Nicotinic Receptors and Calcium Channels in Small Cell Lung Carcinoma: Functional Role, Modulation, and Autoimmunitya

“…Our results suggest that 37 bovine chromaffin high threshold (?) Kim et al 39 rat thyroid C cell line high threshold Grassi et al 40 human neuroblastoma N, L, T Smith et al 34 murine NMJ (extracellular) non-L Viglione et al 20 human SCLC P/Q, L Magnelli et al 43 rat insulinoma P/Q, L Meriney et al 23 human SCLC N, L, P/Q Garcia et al 41 murine DRG T; high threshold Garcia & Beam 42 murine motoneuron T; non-L, L spared murine cardiac myocytes T and L spared murine skeletal myotubes T and L spared both N-and P/Q-type VOCCs are downregulated by LEMS sera (FIGURE 6). Furthermore, significant inhibition of both T-and L-type VOCCs was also observed.…”

“…36 The effects of LEMS antibodies were also studied on the Ca 2+ currents of patchclamped cells (TABLE 1). LEMS antibodies have been reported to inhibit Ca 2+ currents in bovine chromaffin cells, 37 NG108 rat glioma/mouse neuroblastoma cells, 38 thyroid C cells, 39 IMR32 human neuroblastoma cells, 40 murine DRG cells, 41 murine motoneurons, 42 SCLC cells, 20,23 and RINm5F rat insulinoma cells. 43 Some of our results on the effects of LEMS antibodies in IMR32 and RINm5F cells are summarized below.…”

Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions

“…The ‘recruitment’ of a DHP‐sensitive L‐type VDCC component in LEMS IgGs‐treated mice NMJs as well as in LEMS IgGs‐treated mice motoneurons has been previously reported (Smith et al ., 1995; Garcia & Beam, 1996; Xu et al ., 1998). However, DHP drugs are known to be non‐selective Ca 2+ channel blockers when used at micromolar concentrations (Diochot et al ., 1995).…”

Amyotrophic lateral sclerosis: Serum factors enhance spontaneous and evoked transmitter release at the neuromuscular junction

“…This contrasts with the function of autoantibodies in the Lambert-Eaton syndrome (LES), a motor nerve terminal disorder characterized by the downregulation of voltage-gated Ca 2+ channels. 8,26,34 In LES, the elementary properties of the individual Ca 2+ channels are not affected by the antibodies, rather the number of functional Ca 2+ channels is reduced. 17 Furthermore, the ALS Ig acts by producing a ''pharmacological'' facilitation of the Ca 2+ influx, whereas LES antibodies act via antigenic modulation of the channels.…”