RIM proteins tether Ca²⁺ channels to presynaptic active zones via a direct PDZ-domain interaction

At a synapse, fast synchronous neurotransmitter release requires localization of Ca²⁺ channels to presynaptic active zones. How Ca²⁺ channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active-zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca²⁺ channels but not L-type Ca²⁺ channels. To test the physiological significance of this interaction, we generated conditional knockout mice lacking all multidomain RIM isoforms. Deletion of RIM proteins ablated most neurotransmitter release by simultaneously impairing the priming of synaptic vesicles and by decreasing the presynaptic localization of Ca²⁺ channels. Strikingly, rescue of the decreased Ca²⁺-channel localization required the RIM PDZ domain, whereas rescue of vesicle priming required the RIM N terminus. We propose that RIMs tether N- and P/Q-type Ca²⁺ channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse.