AMPA-type glutamate receptors are tetrameric cation channels that mediate the primary depolarization and fast synaptic transmission in vertebrate nervous systems. AMPARs assemble from four subunits, GluR1-4, in various combinations. The subunit composition determines channel function and channel traffic to synapses and is therefore a prime determinant underlying the efficacy and plasticity of glutamatergic neurotransmission (Greger and Esteban, Current Opinion Neurobiol., Vol 17, in press). Mechanisms underlying assembly are understood poorly.

We have shown that RNA editing sites, located at strategic subunit interfaces modulate subunit assembly (Greger et al., 2003, Neuron 40, pp763; Greger et al., 2006, Neuron 51, pp. 85). Both, editing at the R/G (arginine/glycine) sites as well as alternative splicing (flip to flop) in the ligand binding domain are developmentally controlled RNA processing events that impact on assembly as well as on gating. Recent experiments reveal that mutations that lock the channel in various conformational states, which resemble gating transitions alter the kinetics of AMPAR ER-transit. Therefore, conformational alterations resembling gating motions of synaptic AMPARs are sensed by the ER quality control machinery. We suggest that RNA processing sites impact on conformational transitions, and by modulating ER dwell times of subunit confomers determine the formation of AMPAR heteromers.

I acknowlege Pearl Akamine and Stephen Williams for essential contributions as well as the the Royal Society and the MRC for funding.