Related Experiment Video

Updated: Aug 29, 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

Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and

Ella Bossy-Wetzel1, Maria V Talantova, Wilson D Lee

  • 1Center for Neuroscience & Aging, The Burnham Institute, La Jolla, CA 92037, USA. ebossy-wetzel@burnham.org

Neuron
|February 10, 2004
PubMed

Insights

Nitric oxide (NO) and zinc (Zn2+) interact to cause neuronal death in brain conditions. This NO-Zn2+ pathway involves reactive oxygen species and mitochondrial dysfunction, leading to neurodegeneration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) and zinc (Zn2+) play roles in brain ischemia and neurodegenerative diseases.
  • The precise relationship and molecular mechanisms underlying their neurotoxic effects are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism linking nitric oxide and zinc in neuronal apoptosis.
  • To investigate the signaling pathway initiated by nitric oxide that involves zinc release and subsequent cell death.

Main Methods:

  • Utilized cerebrocortical neurons treated with exogenous NO or NMDA.
  • Measured peroxynitrite formation, intracellular zinc release, mitochondrial function (respiratory block, mPT, cytochrome c release), reactive oxygen species (ROS) generation, p38 MAP kinase activation, and K+ efflux.
  • Assessed the effects of Zn2+ chelators, ROS scavengers, Bcl-xL, p38 inhibitors, and K+ channel blockers.

Main Results:

  • Exogenous NO or NMDA induced peroxynitrite formation, leading to intracellular Zn2+ release in neurons.
  • Released Zn2+ triggered mitochondrial dysfunction, ROS production, p38 MAP kinase activation, and caspase-independent K+ efflux.
  • This cascade resulted in cell volume loss and apoptotic-like neuronal death.
  • Inhibitors of Zn2+ release, ROS, p38 MAPK, and K+ channels protected neurons from NO-induced apoptosis.

Conclusions:

  • Established a novel crosstalk between nitric oxide and zinc signaling pathways in neuronal apoptosis.
  • This NO-Zn2+ interaction contributes to neurodegeneration, offering potential therapeutic targets.

Related Concept Videos

Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...
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,...
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...
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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Overview of Cell Death01:30

Overview of Cell Death

Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...