The path that receptors, channels and other synaptic molecules must follow to reach their final destination is not as straightforward as one could imagine. A plethora of proteins that are responsible for the correct assembly of the synapse have been discovered over the past few years, and the identification of new molecules does not show signs of slowing down. The latest addition to the list is stargazin, a protein involved in AMPA-receptor targeting.

Stargazin is the protein defective in the so-called stargazer mutant mice, a strain characterized by the presence of seizures and ataxic gait. As stargazin is slightly homologous to a calcium channel subunit, it was suspected that the effect of the mutation involved changes in channel activity. However, as Chen et al. report now in Nature, stargazin can bind to PSD-95 and other synaptic proteins, as well as to several AMPA-receptor subunits in culture, interactions that seem necessary for targeting AMPA receptors to the membrane. Stargazin-deficient cells lack surface AMPA receptors and AMPA-receptor-mediated synaptic currents, phenotypes that can be rescued by stargazin transfection.

A notable result from this study is that when the interaction between stargazin and PSD-95 is disrupted, AMPA receptors can still reach the membrane but not the synapse. Does this imply that AMPA-receptor targeting by stargazin involves two separate steps, first to the membrane and then to the synapse? To answer this question it will be useful to find out whether the three proteins already form a complex in the Golgi apparatus or whether they assemble only after reaching the cell membrane. Similarly, it will be important to determine under what conditions stargazin binds to AMPA receptors in the intact brain, an interaction that Chen et al. were not able to document. Last, it is noteworthy that AMPA receptors can directly bind PDZ-domain-containing proteins such as PSD-95. Why, then, is stargazin needed at all? What is its specific role? The answer to these questions may require additional guidance from the stars.