Related Experiment Video

Updated: Aug 21, 2026

Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
10:36

Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons

Published on: November 6, 2017

The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: implications for necrosis initiation

Laura Bianchi1, Beate Gerstbrein, Christian Frøkjaer-Jensen

  • 1Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, A232 Nelson Biological Laboratories, 604 Allison Road, Piscataway, New Jersey 08854, USA.

Nature Neuroscience
|November 16, 2004
PubMed

Insights

Hyperactivated MEC-4 sodium channels cause neuronal death by allowing calcium entry and endoplasmic reticulum release. This calcium influx through the MEC-4 channel triggers further release, leading to neurotoxicity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Ion Channel Physiology

Background:

  • The MEC-4 sodium channel (MEC-4(d)) in C. elegans causes neuronal necrosis via increased intracellular calcium and calpain activation.
  • The precise mechanism by which excessive sodium channel activity leads to toxic calcium rise has been unclear.

Purpose of the Study:

  • To investigate the role of voltage-gated calcium channels (VGCCs) in MEC-4(d)-induced neurotoxicity.
  • To elucidate the direct role of the MEC-4(d) channel in calcium influx and subsequent neuronal death.

Main Methods:

  • Heterologous expression of MEC-4(d) in Xenopus oocytes.
  • In vivo studies using C. elegans touch neurons.
  • Utilized the Cameleon calcium sensor to monitor intracellular calcium dynamics.
  • Investigated the role of endoplasmic reticulum (ER) calcium release.

Main Results:

  • Ruled out a critical requirement for VGCCs in MEC-4(d)-induced neurotoxicity.
  • Demonstrated that the MEC-4(d) channel itself conducts calcium ions.
  • Showed that induced release of ER calcium is essential for the progression of necrosis.
  • Identified calcium influx through MEC-4(d) as the trigger for calcium-induced calcium release from the ER.

Conclusions:

  • MEC-4(d) channels directly mediate calcium influx, contributing to neuronal necrosis.
  • A model is proposed where MEC-4(d) channel activity initiates a toxic calcium cascade involving ER release.
  • This mechanism may be relevant to mammalian neurotoxicity, such as that seen with ASIC1a channel activation during ischemia.

More Related Videos

Modeling Age-Associated Neurodegenerative Diseases in Caenorhabditis elegans07:04

Modeling Age-Associated Neurodegenerative Diseases in Caenorhabditis elegans

Published on: August 15, 2020

Related Concept Videos

Cellular Injury IV: Necrosis01:16

Cellular Injury IV: Necrosis

Necrosis is a form of irreversible cell death caused by severe injury such as ischemia, toxins, or trauma. Unlike programmed cell death, it is an uncontrolled, pathological process that typically provokes inflammation in surrounding tissues.Pathophysiologic ChangesNecrosis begins when cells sustain critical damage, leading to swelling of organelles, particularly mitochondria, and rapid ATP depletion. As energy levels decline, membrane ion pumps fail, leading to calcium influx and eventually,...
Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
Necrosis01:16

Necrosis

Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
Secondary Spinal Cord Injury llI: Pathophysiology01:25

Secondary Spinal Cord Injury llI: Pathophysiology

Early Ischemia and Ionic ImbalanceWithin minutes of spinal cord injury, a secondary cascade begins, progressing over hours to weeks. Vascular damage reduces blood flow, causing ischemia and mitochondrial dysfunction. ATP depletion leads to ion pump failure, membrane depolarization, sodium influx, potassium efflux, and water accumulation, resulting in cellular swelling. Increased intracellular calcium further disrupts mitochondria and accelerates cellular injury.Excitotoxicity and Neuronal...
Chemical Synapses01:26

Chemical Synapses

Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
Chemical Synapses01:26

Chemical Synapses

Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...