RIM-binding proteins recruit BK-channels to presynaptic release sites adjacent to voltage-gated Ca²⁺-channels

The active zone of presynaptic nerve terminals organizes the neurotransmitter release machinery, thereby enabling fast Ca²⁺-triggered synaptic vesicle exocytosis. BK-channels are Ca²⁺-activated large-conductance K⁺-channels that require close proximity to Ca²⁺-channels for activation and control Ca²⁺-triggered neurotransmitter release by accelerating membrane repolarization during action potential firing. How BK-channels are recruited to presynaptic Ca²⁺-channels, however, is unknown. Here, we show that RBPs (for RIM-binding proteins), which are evolutionarily conserved active zone proteins containing SH3- and FN3-domains, directly bind to BK-channels. We find that RBPs interact with RIMs and Ca²⁺-channels via their SH3-domains, but to BK-channels via their FN3-domains. Deletion of RBPs in calyx of Held synapses decreased and decelerated presynaptic BK-currents and depleted BK-channels from active zones. Our data suggest that RBPs recruit BK-channels into a RIM-based macromolecular active zone complex that includes Ca²⁺-channels, synaptic vesicles, and the membrane fusion machinery, thereby enabling tight spatio-temporal coupling of Ca²⁺-influx to Ca²⁺-triggered neurotransmitter release in a presynaptic terminal.