CrossTalk opposing view: TARPs modulate AMPA receptor conformations before the gating transitions

摘要

The structural mechanisms of gating for ionotropic glutamate receptors are, arguably, better understood than other ligand-gated ion channels. Based on detailed electrophysiological, computational and crystallographic study, there is a plausible framework for the structural basis of gating in these channels, especially AMPA receptors (Traynelis et al. 2010). The accepted model is that they assemble as a dimer of dimers, with each subunit possessing a clamshell-like ligand-binding domain (LBD) braced against its neighbour. Agonist binding in this clamshell leads the cleft to clamp down around the ligand (state AR in Fig. 1). This agonist-bound cleft-closed dimer-intact state may represent an unstable pre-open conformation (state AR* in Fig. 1) from which the AMPA receptor (AMPAR) has three routes of escape. The upper lobe can swing down, breaking the dimer interface apart and leaving the agonist bound but the channel non-responsive (i.e. desensitized, AD in Fig. 1); the lower lobe can swing up, pulling open the pore and leading to channel activation (state AO); or the cleft can simply re-open.