AMPAR trafficking is complicated

The team from John Hopkins reported in PNAS a new pathway regulating the trafficking of AMPA receptor subunit GluA1. It involves previously unknown phosphorylation of the receptor by PAK3 kinase. However, the mechanism is not straightforward and some controversial data are reported. It appears that stimulation of EphrinB2, another player in activity-based synaptogenesis, leads to phosphorylation of the GluA1 subunits and increases the recruitment of them to the synaptic membrane. On the other hand, mutation of serine S863, which is supposed to be phosphorylated, to alanine or aspartate leads to the same increased surface recruitment of the subunit. The latter can be explained by similarity of carboxylic group to phosphorylated serine, but alanine is the obvious outlier.

All in all, the discovery of PAK3 as the AMPA trafficking regulator is unambiguous and may provide a mechanistic rationale for X-linked intellectual disability. But data are still insufficient to build a robust regulatory pathway, and in my opinion the scheme proposed by the authors doesn’t explain all the observations.