A Trio of Active Zone Proteins Comprised of RIM-BPs, RIMs, and Munc13s Governs Neurotransmitter Release

At the presynaptic active zone, action-potential-triggered neurotransmitter release requires that fusion-competent synaptic vesicles are placed next to Ca²⁺ channels. The active zone resident proteins RIM, RBP, and Munc13 are essential contributors for vesicle priming and Ca²⁺-channel recruitment. Although the individual contributions of these scaffolds have been extensively studied, their respective functions in neurotransmission are still incompletely understood. Here, we analyze the functional interactions of RIMs, RBPs, and Munc13s at the genetic, molecular, functional, and ultrastructural levels in a mammalian synapse. We find that RBP, together with Munc13, promotes vesicle priming at the expense of RBP's role in recruiting presynaptic Ca²⁺ channels, suggesting that the support of RBP for vesicle priming and Ca²⁺-secretion coupling is mutually exclusive. Our results demonstrate that the functional interaction of RIM, RBP, and Munc13 is more profound than previously envisioned, acting as a functional trio that govern basic and short-term plasticity properties of neurotransmission.