Accessories assist AMPA receptors to close pockets

Stargazin (STZ), the prototypical member of the transmembrane AMPA receptor regulatory protein (TARP) family, can boost AMPA receptor activity to enhance synaptic currents as much as one third. The effects of STZ on microscopic and macroscopic AMPA receptor currents are consistent with a mechanism in which STZ facilitates opening of the AMPA receptor channel. However, the mechanism whereby this occurs is unclear. One hypothesis, largely based on structural models of AMPA receptor activation, is that STZ promotes closure of the cleft in the ligand-binding domain (LBD) of AMPA receptor, a conformation that more closely resembles that of the agonist-bound receptor structure (Armstrong and Gouaux, 2000). Two groups with complementary expertise, Howe and Jayaraman, teamed up to test this hypothesis (MacLean et al., 2014). They performed a series of challenging electrophysiological analyses and spectroscopic measurements and report the first direct evidence that indeed, in the presence of STZ, the agonistbinding cleft of AMPA receptor is more closed, regardless of whether or not glutamate is present. In addition to providing valuable evidence for a physiologically important neuromodulatory mechanism, this study is noteworthy for the elegance with which it bridges the still sizeable gap between structural and kinetic models of AMPA receptor activation. Such combined approaches hold the key to achieving an integrated view of how synaptic responses in the central nervous system arise and are modulated.