Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

AMPA receptors are glutamate-gated cation channels assembled from GluA1-4 subunits and have properties that are strongly dependent on the subunit composition. The subunits have different propensities to form homomeric or various heteromeric receptors expressed on cell surface, but the underlying mechanisms are still poorly understood. Here, we examined the biochemical basis for the poor ability of GluA3 subunits to form homomeric receptors, linked previously to two amino acid residues, Y454 and R461, in its ligand-binding domain (LBD). Surface expression of GluA3 was improved by co-assembly with GluA2 but not with stargazin, a trafficking chaperone and modulator of AMPA receptors. The secretion efficiency of GluA2 and GluA3 LBDs paralleled the transport difference between the respective full-length receptors and was similarly dependent on Y454/R461, but not on LBD stability. In comparison to GluA2, GluA3 homomeric receptors showed a strong and Y454/R461-dependent tendency to aggregate both in the macroscopic scale measured as lower solubility in nonionic detergent and in the microscopic scale evident as the preponderance of hydrodynamically large structures in density gradient centrifugation and native gel electrophoresis. We conclude that the impaired surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation to which LBD residues Y454 and R461 strongly contribute. This aggregation inhibits the entry of newly synthesized GluA3 receptors to the secretory pathway.

Reconceptualising International Intervention: Statebuilding, ‘Organic Processes’ and the Limits of Causal Knowledge

This article examines the transformation in the conceptual understanding of international intervention over the last two decades. It suggests that this conceptual shift can be usefully interrogated through its imbrication within broader epistemological shifts highlighting the limits of causal knowledge claims: heuristically framed in this article in terms of the shift from policy interventions within the problematic of causation to those concerned with the management of effects. In this shift, the means and mechanisms of international intervention have been transformed, no longer focused on the universal application of Western causal knowledge through policy interventions but rather on the effects of specific and unique local and organic processes at work in societies themselves. The focus on effects takes the conceptualisation of intervention out of the traditional terminological lexicon of International Relations theory and instead recasts problems in increasingly organicised ways, suggesting that artificial or hubristic attempts at socio-political intervention should be excluded or minimised.