The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders

The abnormal influx of Ca2+ through glutamate receptor channels is thought to contribute to the loss of neurons associated with a number of brain disorders. Until recently, the NMDA receptor was the only glutamate receptor known to be Ca2+-permeable. It is now well established that AM PA receptors exist not only in Ca2+-impermeable but also in Ca2+-permeable forms. AMPA receptors are encoded by four genes designated gluRI (gluR-A) through gluR4 (gluR-D). The presence of the gloR2 subunit renders heteromeric AMPA receptor assemblies Ca2+-impermeable, Recent studies involving animal models of transient forebrain ischemia and epilepsy show that gluR2 mRNA is downregulated in vulnerable neurons. These observations suggest that downregulation of gluR2 gene expression may serve as a 'molecular switch' leading to the formation of Ca2+-permeable AMPA receptors and enhanced toxicity of endogenous glutamate following a neurological insult.