The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain

Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are comprised of different combinations of GluA1-GluA4 (also known asGluR1-GluR4 and GluR-A to GluR-D) subunits. The GluA2 subunit is subject to RNA editing by the ADAR2 enzyme, which converts a codon for glutamine (Gln; Q), present in the GluA2 gene, to a codon for arginine (Arg; R) found in the mRNA. AMPA receptors are calcium (Ca(2+))-permeable if they contain the unedited GluA2(Q) subunit or if they lack the GluA2 subunit. While most AMPA receptors in the brain contain the edited GluA2(R) subunit and are therefore Ca(2+)-impermeable, recent evidence suggests that Ca(2+)-permeable AMPA receptors are important in synaptic plasticity, learning, and disease. Strong evidence supports the notion that Ca(2+)-permeable AMPA receptors are usually GluA2-lacking AMPA receptors, with little evidence to date for a significant role of unedited GluA2 in normal brain function. However, recent detailed studies suggest that Ca(2+)-permeable AMPA receptors containing unedited GluA2 do in fact occur in neurons and can contribute to excitotoxic cell loss, even where it was previously thought that there was no unedited GluA2.This review provides an update on the role of GluA2 RNA editing in the healthy and diseased brain and summarizes recent insights into the mechanisms that control this process. We suggest that further studies of the role of unedited GluA2 in normal brain function and disease are warranted, and that GluA2 editing should be considered as a possible contributing factor when Ca(2+)-permeable AMPA receptors are observed.

Keywords: AMPA receptor; GluA2; GluR-B; GluR2; RNA editing; adenosine deaminases acting on RNA; excitotoxicity.

FIGURE 1

Schematic view of AMPA, NMDA, and KA receptors within the postsynaptic density and the AMPA receptor structure. (A) Glutamate in the synaptic cleft can act on ionotropic receptors including AMPA, NMDA, and KA receptors causing a Ca²⁺ influx leading to intracellular signaling cascades. (B) Representation of the primary structure of AMPA receptor subunits with N- and C-terminals, four membranes, M1–M4 (gray boxes), two editing sites, Q/R and R/G (violet dots), and alternate spliced flip/flop site (violet box). A summary of glutamate receptors and their subunits are also shown. Subunits shown in violet are subunits that undergo RNA editing at the Q/R site. (C) Topology (secondary structure) of the GluA2 subunit with three transmembrane domains. The Q/R RNA editing site controls Ca²⁺-permeability of the AMPA receptor site and is located in the putative second membrane domain. The R/G site and flip/flop sites, which control desensitization of the receptor, are located prior to the fourth membrane domain. The protein sequence of GluA2 varies by one codon, arginine (Arg), from GluA1, GluA3, and GluA4, which express a glutamine (Gln). The arginine is post-transcriptionally introduced by an amino acid change in the pre-mRNA of GluA2 by RNA editing. (D) Current response in normal Ringer solution and Ca²⁺-Ringer solution of oocytes injected with GluA1 cRNA (left) or GluA1+GluA2 cRNA (right). Oocytes containing GluA2 eliminated the inward current, thus showing GluA2 regulates Ca²⁺-permeability of the AMPA receptor. Reprinted from Hollmann et al. (1991), with permission.

FIGURE 2

AMPA receptors containing GluA2 are Ca²⁺-impermeable due to editing at the Q/R site. (A) Current understanding of the quaternary structure of AMPA receptors, thought to be tetrameric assemblies of four AMPA receptor subunits form the ion channel pore. The assembled receptor can comprise any combination of GluA1–GluA4 subunits but usually contains GluA2. Reprinted from Sobolevsky et al. (2009), with permission. (B) AMPA receptors generally contain GluA2 (red) with combinations of GluA1, GluA3, and GluA4 (blue). AMPA receptors containing edited GluA2 are impermeable to Ca²⁺ (left). AMPA receptors containing unedited GluA2 and AMPA receptors lacking GluA2 are Ca²⁺-permeable (right).