Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS

  title={Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS},
  author={Yukio Kawahara and Shin Kwak and Hui Sun and Kyoko Ito and Hideji Hashida and Hitoshi Aizawa and Seon‐Yong Jeong and Ichiro Kanazawa},
  journal={Journal of Neurochemistry},
AMPA receptor‐mediated neurotoxicity is currently the most plausible hypothesis for the etiology of amyotrophic lateral sclerosis (ALS). The mechanism initiating this type of neuronal death is believed to be exaggerated Ca2+‐influx through AMPA receptors, which is critically determined by the presence or absence of the glutamate receptor subunit 2 (GluR2) in the assembly. We have provided the first quantitative measurements of the expression profile of AMPA receptor subunits mRNAs in human… 

Excitotoxicity and ALS: What is unique about the AMPA receptors expressed on spinal motor neurons?

  • Y. KawaharaS. Kwak
  • Biology
    Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases
  • 2005
This review focuses on recent progress on the molecular dynamics of AMPA receptors and discusses the pathophysiology of selective motor neuron death mediated by AM PA receptors in individuals affected with sporadic ALS.

Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity

To the knowledge, this is the first demonstration of presymptomatic changes in trafficking of receptors that are in direct control of excitotoxicity and death in a mouse model of ALS.

Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis

GluR2 underediting occurs in a disease specific and region selective manner and is likely that the molecular mechanism underlying the deficiency in RNA editing is a reduction in the activity of ADAR2, a double- strand RNA specific deaminase.

Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity

The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptor-mediated excitotoxicity, revealing a mechanism through which astroCytes influence neuronal functioning in health and disease.

GluR2 Deficiency Accelerates Motor Neuron Degeneration in a Mouse Model of Amyotrophic Lateral Sclerosis

It is indicated that GluR2 plays a pivotal role in the vulnerability of motor neurons in vitro and in vivo, and that therapies that limit Ca2+ entry through AMPA receptors might be beneficial in ALS patients.

Sub-cellular localization and regulatory mechanisms of AMPA receptors in motor neurons of a murine model of familial Amyotrophic Lateral Sclerosis

Increased level of the trafficking protein NSF, able to increase the delivery of GluR2 at the cell surface, was reported selectively in the motor neurons at the presymptomatic stage of the disease in SOD1G93A mice, suggesting that the increase of NSF may be an attempt to protect motor neurons from excitotoxicity by maintaining the sufficient levels of GLUR2 subunit in the membrane.



GluR2 AMPA Receptor Subunit Expression in Motoneurons at Low and High Risk for Degeneration in Amyotrophic Lateral Sclerosis

Exchange of GluR2 mRNA and protein in motoneurons that differ in their vulnerability to degeneration in ALS suggests that reduced expression of GLUR2 is not a factor predisposing mot oneurons to degenerations.

AMPA Receptor Calcium Permeability, GluR2 Expression, and Selective Motoneuron Vulnerability

The results indicate that the selective vulnerability of motoneurons to AMPA receptor agonists is not determined solely by whole-cell relative Ca2+ permeability of AMPA receptors.

Characterization of the AMPA‐Activated Receptors Present on Motoneurons

The data show that despite high levels of edited GluR2 mRNA, some AMPARs are Ca2+‐permeable, and this subset of AM PARs can account for the AMPAR‐mediated Ca2- inflow inferred from cobalt uptake and electrophysiology studies.

Analysis of AMPA receptor subunit mRNA expression in control and ALS spinal cord.

Examination of mRNAs for the subunits of the AMPA type of glutamate receptor (GluR A, B, C and D) in control human spinal cord using in situ hybridization and in parallel the expression in patients with sporadic amyotrophic lateral sclerosis revealed a significant decrease in mRNA levels in ALS spinal cord compared with controls.

Low expression of GluR2 AMPA receptor subunit protein by human motor neurons.

It is likely that human motor neurons express a high proportion of atypical, calcium permeable AMPA receptors which may contribute to selective vulnerability and may allow cell-specific modulation of the actions of glutamate.

The Influence of Glutamate Receptor 2 Expression on Excitotoxicity in GluR2 Null Mutant Mice

AMPA receptor (AMPAR)-mediated ionic currents that govern gene expression, synaptic strength, and plasticity also can trigger excitotoxicity. However, native AMPARs exhibit heterogeneous

Light and electron microscopic distribution of the AMPA receptor subunit, GluR2, in the spinal cord of control and G86R mutant superoxide dismutase transgenic mice

The results suggest that the cellular and synaptic distribution of GluR2 is not a determinant of the selective vulnerability observed in SOD‐1 transgenic mice or in ALS patients.

AMPA Receptor Current Density, Not Desensitization, Predicts Selective Motoneuron Vulnerability

It is suggested that the greater AMPA receptor current density of spinal motoneurons may be sufficient to account for their selective vulnerability to AMPA receptors agonists in vitro.

Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis

The decrement of GluR2 mRNA editing efficiency is unique to the ventral gray of ALS cases and may be closely linked to the etiology of ALS.

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated Injury In Vitro

Large SMI-32(+) neurons are selectively damaged by prolonged (24 hr) low-level exposures to kainate or to the glutamate reuptake blockerl-trans-pyrrolidine-2,4-dicarboxylic acid, suggesting that Ca2+ ions are also important in this more slowly evolving injury.