Amyotrophic lateral sclerosis IgG-treated neuromuscular junctions develop sensitivity to L-type calcium channel blocker

Abstract

In order to search for early changes induced by the application of human immunoglobulin G (IgG) on motor nerve terminals, IgG from patients with amyotrophic lateral sclerosis (ALS) and control subjects was injected subcutaneously into the levator auris muscle of mice. A week or a month after the last injection, endplate potentials were recorded. No changes in quantal content of transmitter release were observed. In control and ALS IgG-treated muscles, neurotransmitter release remained sensitive to P/Q-type and insensitive to N-type voltage-sensitive calcium channel (VSCC) blockers as in untreated muscles. In contrast, IgG from 5 of 8 different ALS patients induced a significant reduction in quantal content of the evoked response after incubation with nitrendipine, indicating that a novel sensitivity to this calcium channel blocker appears in these motor nerve terminals. These results indicate that ALS IgG induces plastic changes at nerve terminals. Amyotrophic lateral sclerosis (ALS) is the most common human motor neuron disease. Affected individuals show progressive dysfunction and degeneration of brain, brainstem, and spinal cord motor neurons, clinically manifested as progressive muscular weakness, paralysis, and death within a mean of 3 years. 35 There is no cure available for this disease and its pathophysiology remains unclear.Electrophysiological studies of muscle biopsies from ALS patients have revealed severe presynaptic impairment of neuromuscular transmission. 16 In addition, some endplates show signs of immaturity, in accordance with the process of degeneration and regeneration known to occur in this disease. 25There is general agreement that the selective death of motoneurons results from a cascade of toxic biological events triggered by a variety of factors. ALS can be considered a multifactorial disorder that includes a population of genetically predisposed patients. Sporadic ALS accounts for approximately 90% of reported cases and familial cases constitute 5-10%. 5,27,28 In sporadic ALS patients, motoneuron

Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

“…Additionally, ALS-IgG consistently increased transmitter release in different NMJ preparations, including diaphragm muscle (Uchitel et al, 1988;O'Shaughnessy et al, 1998;Mohamed et al, 2002;Muchnik et al, 2002) and levator auris muscle of the mouse (Uchitel et al, 1992;Fratantoni et al, 2000) and guinea pig diaphragm muscle (O. D. Uchitel, unpublished results) and even in hippocampal cellular culture (Andjus et al, 1997). It did not increase transmitter release, however, in PC12 cells (Offen et al, 1998) and mouse extraocular NMJ (Mosier et al, 2000).…”

“…The electrophysiological equipments used have been described previously (Fratantoni et al, 2000). Borosilicate glass capillaries were used for microelectrodes filled with 3 M KCl (20 -35 M⍀ resistance).…”

“…Interestingly, some of this evidence correlates with observations made in research animals. In rodents treated with IgG from ALS patients (ALS-IgG), a [Ca 2ϩ ] i increment associated with degenerative structural alterations in motoneurons and synaptic plasticity at neuromuscular transmission was also observed (Engelhardt et al, 1995;Fratantoni et al, 2000;Pullen and Humphreys, 2000;Pullen et al, 2004). ALS-IgG from ϳ50% of ALS patients trigger synaptic potentiation in spontaneous neuromuscular transmission, together with [Ca 2ϩ ] i increment (ex vivo), and can induce long-term neuromuscular dysfunction in vivo (Uchitel et al, 1988(Uchitel et al, , 1992Engelhardt et al, 1995;O'Shaughnessy et al, 1998;Mohamed et al, 2002).…”

Immunoglobulins G from patients with sporadic amyotrophic lateral sclerosis affects cytosolic Ca2+ homeostasis in cultured rat astrocytes

“…Several studies have highlighted the relationship between high levels of glutamate released by nerve terminals and an increase in intracellular free calcium due to ALS IgG action on ligand and/or voltage-gated Ca 2+ channels [10][11][12][13][14][15]. In addition, neuronal death due to excitotoxicity has been suggested as the basis of the etiopathogenesis of ALS.…”

The functional role of laminins-α4 and -β2 in development of the neuromuscular junction

“…It was found that this toxin significantly impaired neurotransmission, by preventing Ca 2+ influx through N-type VGCCs at P8 but not at P14, when the NMJ has developed to maturity and switched to P/Q-type VGCC mediated transmitter release. Both L-and R-type VGCCs have also been implicated in having a minor role in the release of ACh at healthy NMJ (Rosato-Siri & Uchitel, 1999;Correia-deSa et al, 2000a, b;Urbano et al, 2003), while L-type VGCCs also play a role in transmitter release under pathological conditions such as amyotrophic lateral sclerosis (Fratantoni et al, 2000) and in botulinum toxic poisoning (Santafe et al, 2000).…”