RIM CB Domains Target Presynaptic Active Zone Functions to PIP-Containing Membranes.

Rapid and efficient synaptic vesicle fusion requires a pool of primed vesicles, the nearby tethering of Ca channels, and the presence of the phospholipid PIP in the target membrane. Although the presynaptic active zone mediates the first two requirements, it is unclear how fusion is targeted to membranes with high PIP content. Here we find that the CB domain of the active zone scaffold RIM is critical for action potential-triggered fusion. Remarkably, the known RIM functions in vesicle priming and Ca influx do not require RIM CB domains. Instead, biophysical experiments reveal that RIM C domains, which lack Ca binding, specifically bind to PIP. Mutational analyses establish that PIP binding to RIM CB and its tethering to the other RIM domains are crucial for efficient exocytosis. We propose that RIM CB domains are constitutive PIP-binding modules that couple mechanisms for vesicle priming and Ca channel tethering to PIP-containing target membranes.