AMPA Receptors: Players in Calcium-Mediated Neuronal Injury?

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AMPA receptors mediate a majority of fast, excitatory neurotransmissions in the CNS. AMPA receptors are multimeric proteins composed of one or more of four subunits, termed GluR1-4. Structure-function studies using recombinant AMPA receptor subunits have demonstrated the importance of an arginine residue at the Q/R site within the second transmembrane domain of the GluR2 subunit in conferring the selectivity of the receptor for monovalent cations. Native AMPA receptors in the adult, mammalian CNS are multimeric proteins that are largely calcium-impermeable because of the presence of the dominant GluR2 subunit. Populations of cells in both the developing and adult brain, however, express AMPA receptors that lack the GluR2 subunit and thus are cal cium-permeable. The function of these calcium-permeable AMPA receptors (CPARs) is unknown. Such cells may, however, be selectively vulnerable to excitotoxic injury. After severe global cerebral ischemia in rats, GluR2 expression is selectively downregulated in the vulnerable CA1 region of the hippocampus before the onset of ischemic cell death. Thus AMPA receptor activation may contribute to the excessive accumulation of intra cellular calcium that is thought to mediate irreversible cell injury. This article reviews the molecular basis of CPARs and discusses their possible role in mediating excitotoxic injury. NEUROSCIENTIST 4:149-153, 1998