CAST (green) and Bassoon (red) colocalize at the early stages of synapse formation.

For the nervous system to function properly, neurotransmitters must be released in a regulated fashion from an active zone in the presynaptic membrane, but relatively little is known about how synaptic vesicles are directed to this zone in the first place. On page 577, Ohtsuka et al. characterize a novel protein associated with the active zone.

The cytomatrix at the active zone (CAZ) is believed to be important in determining synaptic vesicle localization. In the new work, the authors began with traditional biochemistry, comparing crude membrane and postsynaptic density fractions from rat brain to identify proteins associated with the synapse. One novel protein was found and named CAZ-associated structural protein (CAST). Electron microscopy places CAST at the CAZ in conventional synapses. CAST associates with two known CAZ proteins, RIM1 and Munc13–1, in a ternary complex that associates with the CAZ protein bassoon, providing the first evidence that CAZ proteins form a network of protein–protein interactions in vivo.

CAST appears to help determine RIM1 localization in neurons, and the authors found that CAST is expressed in the early stages of synapse formation in primary cultured neurons. The data suggest that complexes of CAZ proteins associate with vesicles during the early stages of synapse formation, and that these protein–vesicle complexes are then transported to the newly forming synapses. Fusion of the vesicles with the plasma membrane could then determine the location of the new active zone.

A database search uncovered a putative orthologue of CAST in C. elegans, suggesting that the new protein is a conserved component required for CAZ formation in metazoans. If so, then targeted disruption of CAST in mice or worms should provide additional insight into the formation of this crucial structure. ▪