Characterization of alternatively spliced isoforms of AMPA receptor subunits encoding truncated receptors.
Molecular and Cellular Neuroscience. 2008-02-01; 37(2): 323-334
DOI: 10.1016/j.mcn.2007.10.008
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Glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA)-type play an important role in synaptic plasticity and contribute to
cell death under excitotoxic conditions. AMPA receptors form heterotetramers of
four homologous subunits (GluR1-4), which exist in two functionally different
isoforms, flip and flop, generated by alternative splicing. We identified
transcripts for alternatively spliced isoforms of AMPA receptor subunits which
lack both the flip and the flop exons, in hippocampal and retinal cultures. These
transcripts originate AMPA receptor subunits lacking the flip/flop cassette, the
fourth transmembrane domain and the intracellular C-terminus. Truncated GluR1
associates with full-length GluR1 and exerts a dominant negative effect, giving
rise to non-functional receptors. Moreover, truncated GluR1 reaches the cell
surface, but is not efficiently targeted to the synapse. Hippocampal neuronal
transfection with truncated GluR1 resulted in a significant reduction in
apoptotic neuronal death triggered by toxic concentrations of glutamate.
Furthermore, mRNA coding for the truncated subunits is consistently detected in
some regions of the brain in epileptic rats and in hippocampal neurons submitted
to toxic concentrations of glutamate. The existence of truncated AMPA receptor
subunits may constitute an intrinsic neuroprotective mechanism.