Recent advances in the study of AMPA receptors.

Abstract

As glutamate is a dominant excitatory neurotransmitter in the central nervous system, glutamate receptors, and especially AMPA receptors, are located ubiquitously in all brain areas. In this paper, we reviewed recent advances of studies on AMPA receptor functions. AMPA receptors are cation-conducting complexes composed of various combinations of four subunits (GluR1 to GluR4). The glutamine residue located in the pore-forming segment of GluR2 subunit (Q/R site) is changed to arginine by RNA editing at the pre mRNA stage in normal adult mammalian animal. The edited GluR2 subunit is a major determination of Ca(2+) permeability of the AMPA receptor; only edited GluR2-lacking receptor shows high-Ca(2+) permeability. The assembly of glutamate AMPA receptor subunit is not completely according to the stochastic theory. The heteromeric subunits assembly is more rapid than the homomeric assembly is. The transfer of AMPA receptor subunit to the plasma membrane is conducted in multiple ways. Many molecules that interact with the intracellular domain of AMPA receptor subunits are reported as the modulators of AMPA receptor subunit transfer. In the motoneuron of sporadic amyotrophic lateral sclerosis (ALS) patients, the efficiency of RNA editing at the GluR2 Q/R site is significantly decreased. Relative low level of edited GluR2 subunit expression is likely responsible for motoneuronal death in ALS. Recently, AMPA receptors in glial cells have been studied. Bergmann glial cells in cerebellum express Ca(2+)-permeable AMPA receptors. Conversion of these AMPA receptors to Ca(2+)-impermeable type receptors induces morphological and functional changes. Glioblastoma cells also express Ca(2+)-permeable AMPA receptors, and their conversion to Ca(2+)-impermeable receptors inhibits cell locomotion and induces apoptosis.

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2

“…Recently, we demonstrated that a significant proportion of GluR2 mRNA was unedited at the Q/R site in spinal motor neurons of postmortem patients with sporadic ALS. This is in marked contrast to the fact that all GluR2 mRNA was edited in the motor neurons of control subjects (Takuma et al, 1999;Kawahara et al, 2004) and of patients with motor neuron diseases other than sporadic ALS (Kawahara et al, 2006), as well as in dying neurons in other neurodegenerative diseases, including Purkinje cells of patients with spinocerebellar degeneration (Paschen et al, 1994;Akbarian et al, 1995;Kawahara et al, 2004;Suzuki et al, 2003). The disease specificity of inefficient GluR2 Q/R site editing implies the pathogenic relevance of ADAR2 insufficiency in the death of motor neurons in sporadic ALS but leaves open the possibility that other genes whose products remain unedited by ADAR2 insufficiency might contribute to the demise of motor neurons.…”

When Does ALS Start? ADAR2?GluA2 Hypothesis for the Etiology of Sporadic ALS

“…This is in marked contrast to the fact that all GluA2 mRNA was edited in the motor neurons of control subjects (Takuma et al, 1999; Kawahara et al, 2004), in patients with motor neuron diseases other than sporadic ALS (Kawahara et al, 2006), and in dying neurons in other neurodegenerative diseases, including the Purkinje cells of patients with spinocerebellar degeneration (Paschen et al, 1994; Akbarian et al, 1995; Suzuki et al, 2003; Kawahara et al, 2004). The high disease specificity warrants an investigation of how inefficient GluA2 RNA editing leads to neuronal death.…”

Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data

“…AMPA receptors are cation-selective tetrameric heterooligomers formed by combinations of the subunits GluR1, GluR2, GluR3, and GluR4 (Hollmann et al 1989;Boulter et al 1990; Keinanen et al 1990; Wisden and Seeburg 1993;Sommer and Seeburg 1992;Fletcher and Lodge 1996;Quirk and Nisenbaum 2002;Suzuki et al 2003;Brorson et al 2004). These subunits are of about 900 amino acids and contain a large extracellular N-terminal domain.…”