Building and breaking interfaces: how a receptor takes shape.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Farina et al. Most ion channels and neurotransmitter receptors assemble into functional hetero-oligomers with precise stoichiometry and composition. Ionotropic glutamate receptors (GluRs), for example, the main mediators of excitatory neurotransmission, are either obligatory NMDA (GluN1-3) or preferential AMPA (GluA1-4) and kainate (GluK1–5) heterotetramers. The extracellu-lar N-terminal domain (NTD) and ligand-binding domain (LBD) of each subunit interact with partner subunits at the level of both the NTD and LBDs to form a dimer-of-dimers in the full-length tetrameric receptor (Mayer, 2011). How different sub-unit pairs are incorporated and others excluded during receptor biogenesis remains largely unresolved, despite the profound consequences that proper ionotropic GluR assembly has for neuronal physiology and pathology. Critical spatiotemporal parameters include distinct subunit expression profiles, local concentrations during initial synthesis in the endoplasmic reticulum (ER) and subsequent diffusion, and relative affinities between subunits. Recent structural and biophysical studies have explored the role of the NTDs in controlling ionotropic GluR subunit assembly. In a recent issue of The Journal of Neuroscience, Farina et al. (2011) show how distinct NTD properties of NMDA receptors, which are arguably the most complex ionotropic GluRs, affect assembly. They identify a novel biosynthetic intermediate that leads to new speculations on how these receptors are assembled in cells. Most GluNs consist of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. Farina et al. (2011) first show that GluN2 requires GluN1 to traffic to the cell surface: GluN2 is only present on the cell surface when coexpressed with wild-type GluN1, but not with an NTD-lacking GluN1 (GluN1⌬NTD). Remarkably, coexpression of isolated GluN1-NTD along with GluN1⌬NTD rescues surface expression of GluN2A. The isolated GluN1-NTD also rescues expression of GluN2A/B-NTD, as a folded soluble protein secreted from the ER, presumably through a direct physical interaction [Farina et al. (2011), their Fig. 1]. Whether the rescued surface expression of GluN2A results in production of a functional receptor remains to be tested with electrophysiological recordings. What happens to receptor assembly if the NTD heterodimer is stabilized? The authors scan for mutations in GluN1-NTD that enhance heterodimerization with the GluN2-NTD and promote its surface expression , using NTD …