Role of the NR2 subunit composition and intracellular C-terminal domain in N-methy-D-aspartate receptor signalling.
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Date
2009Author
Martel, Marc-André
Metadata
Abstract
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ionotropic receptors.
When activated, NMDARs let extracellular sodium and calcium ions enter neurons. This
calcium influx, depending on its duration, intensity and the presence of nearby signalling
proteins can signal to synaptic plasticity. Additionally, physiological NMDAR activity
promotes pro-survival cascades and gene transcription, whereas both lack of activation
and overactivation of these receptors trigger pro-death signals. Several
neurodegenerative pathologies such as stroke/ischemia and Alzheimer’s disease are
thought to involve NMDAR overactivation, so-called “excitotoxicity”, but since
NMDARs are important for normal neuronal physiology, potential therapeutical
approaches needs to go beyond simple antagonism. Here, we studied the receptor
subunit composition and the molecular cascades downstream of the receptor activation
to try and isolate the pro-death pathways in NMDAR-mediated excitotoxicity. We found
that the NR2 subunit composition did not dictate the type of NMDAR-mediated signals,
as receptors comprised of NR2B subunits were able to signal to death, survival and
plasticity. However, we also found that the intracellular tail of the NR2B subunit was
more efficient at triggering neuronal death compared to the NR2A C-terminus, which
suggests that different pro-death signalling complexes are associated to each subunit.
Two pro-death signals, the p38 and c-Jun N-terminal kinase (JNK) cascades, are key
mediators of neuronal excitotoxicity. In a non-neuronal cell line, NMDAR-mediated cell
death could be reconstituted but was found to rely solely on JNK and not p38. This was
due to the lack of pro-death signals from the NR2B-PDZ domain, a cytoplasmic
interacting domain which forms a signalling cassette with the neuronal proteins PSD-95
and neuronal nitric oxide synthase. This PDZ-ligand recruits the p38 cascade in neurons,
but was absent in non-neuronal cells. The pro-death p38 pathway could be inhibited in
neurons by disrupting the PDZ domain interactions, which protects against
excitotoxicity. This disruption was not affecting normal synaptic transmission,
potentiation or survival signalling, suggesting that this could be a therapeutically viable
avenue. Thus, this work has expanded the understanding of how NMDAR subunits and their cytoplasmic domains mediate signalling leading to a variety of cellular outcomes; a
crucial point for the development of a strategy specifically targeting NMDAR- mediated
pro-death signalling.