Each subunit undergoes posttranscriptional modifications involving at least two mechanisms. One of these is the alternative splicing of mRNA. The resulting splice variants called flip (i) and flop (o) result from the splicing out of one of two possible modules within the mRNA. Flip and flop splice variants are responsible for significant structural and functional channel variation on the extracellular side of the membrane preceding TM4 (Figure 1). They are of vital importance in determining the desensitization properties of the receptor/ channel complex. Another source of structural and functional variation is RNA editing at the Q/R and R/G sites in the mRNA. In domain TM2 of GluR1-4, a particular glu-tamine (Q607; codon CAG) may be edited enzymatically to an arginine (R607; codon CIG). This Q/R editing process is regulated by an adenosine deaminase enzyme (ADARA) by yet-unknown mechanisms and is more than 99% efficient in editing GluR2 in almost all brain regions (a physiologically important exception being Bergmann glial cells in the cerebellum), conferring the property of near impermeability to calcium ions, low single-channel conductance, and a nearly linear current-voltage relation. Calcium ion impermeability in most brain regions is essential for survival to prevent excitotoxic injury to neurons. Asingle edited GluR2
subunit in a heteromeric AMPAchannel is sufficient to confer this protection. Recent evidence also shows that GluR2 release from the endoplasmic reticulum seems to be regulated by this editing process, lending dual importance to its role. GluR2-4 are also edited at an additional site called the R/G site, located near the flip/flop coding region, resulting in diminished and more rapid desensitization.
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