Accessories assist AMPA receptors to close pockets

C o m m e n t a r y Stargazin (STZ), the prototypical member of the trans­ membrane 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. How­ ever, 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 ligand­binding domain (LBD) of AMPA receptor, a conformation that more closely resembles that of the agonist­bound 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 agonist­ binding cleft of AMPA receptor is more closed, regard­ less 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 syn­ aptic responses in the central nervous system arise and are modulated. AMPA receptors mediate excitatory neurotransmission in the brain AMPA receptors are glutamate­gated ion channels and a hallmark of central excitatory synapses. Their kinetics are finely tuned to detect the rise and fall of the gluta­ mate concentration in the synaptic cleft; to integrate this chemical signal with extracellular and intracellular cues; and to produce a postsynaptic current whose ampli­ tude and kinetics reflect the totality of this information. The molecular diversity of tetrameric AMPA receptors and the constellation of modulators present at each syn­ apse give rise to the broad diversity of synaptic electric signatures required to meet the specific needs of the tril­ lion excitatory synapses that coexist in an adult (human) brain. Evidence is accumulating that STZ modulates several aspects of AMPA receptor physiology and thus regulates major aspects of the synaptic response. The kinetic properties of the AMPA receptor response are determined primarily by the receptor's specific mo­ lecular composition (Fig. 1 A; Sobolevsky et al., 2009; Traynelis …