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Lambert-Eaton sera reduce low-voltage and high-voltage activated Ca2+ currents in murine dorsal root ganglion neurons
K D García1, M Mynlieff, D B Sanders
1Department of Anatomy and Neurobiology, Colorado State University, Fort Collins 80523, USA.
Abstract:
Voltage-gated Ca2+ channels are categorized as either high-voltage activated (HVA) or low-voltage activated (LVA), and a subtype (or subtypes) of HVA Ca2+ channels link the presynaptic depolarization to rapid neuro-transmitter release. Reductions in transmitter release are characteristic of the autoimmune disorder, Lambert-Eaton syndrome (LES). Because antibodies from LES patients reduce Ca2+ influx in a variety of cell types and disrupt the intramembrane organization of active zones at neuromuscular synapses, specificity of LES antibodies for the Ca2+ channels that control transmitter release has been suggested as the mechanism for disease. We tested sera from four patients with LES. Serum samples from three of the four patients reduced both the maximal LVA and HVA Ca2+ conductances in murine dorsal root ganglion neurons. Thus, even though LES is expressed as a neuromuscular and autonomic disorder, our studies suggest that Ca2+ channels may be broadly affected in LES patients. To account for the specificity of disease expression, we suggest that incapacitation of only a fraction of the Ca2+ channels clustered at active zones would severely depress transmitter release. In particular, if several Ca2+ channels in a cluster are normally required to open simultaneously before transmitter release becomes likely, the loss of a few active zone Ca2+ channels would exponentially reduce the probability of transmitter release. This model may explain why LES is expressed as a neuromuscular disorder and can account for a clinical hallmark of LES, facilitation of neuromuscular transmission produced by vigorous voluntary effort.
Insights
Autoimmune Lambert-Eaton syndrome (LES) antibodies affect voltage-gated calcium channels broadly, not just at neuromuscular junctions. This broad impact explains LES symptoms and the characteristic facilitation seen in patients.
Area of Science:
- Neuroscience
- Immunology
- Channelopathies
Background:
- Voltage-gated calcium channels (VGCCs) are crucial for neurotransmitter release.
- Lambert-Eaton syndrome (LES) is an autoimmune disorder characterized by reduced neurotransmitter release.
- LES antibodies are suspected to target VGCCs specifically at the neuromuscular junction.
Purpose of the Study:
- To investigate the effect of LES patient antibodies on different types of VGCCs.
- To determine if LES antibodies affect VGCCs beyond the neuromuscular junction.
- To propose a mechanism explaining the specific expression of LES symptoms.
Main Methods:
- Tested sera from four Lambert-Eaton syndrome patients.
- Measured maximal low-voltage activated (LVA) and high-voltage activated (HVA) calcium conductances.
- Utilized murine dorsal root ganglion neurons as a model system.
Main Results:
- Sera from three out of four LES patients reduced both LVA and HVA calcium conductances.
- The study suggests a broader impact of LES antibodies on calcium channels than previously assumed.
- LES antibodies appear to affect calcium channels in neurons beyond the neuromuscular junction.
Conclusions:
- Lambert-Eaton syndrome may involve a broader disruption of calcium channels than just those at the neuromuscular junction.
- A model is proposed where the loss of a few clustered active zone calcium channels exponentially reduces neurotransmitter release probability.
- This model explains the neuromuscular expression of LES and the hallmark facilitation observed with increased effort.