Redundant functions of RIM1α and RIM2α in Ca ²⁺-triggered neurotransmitter release

α-RIMs (RIM1α and RIM2α) are multidomain active zone proteins of presynaptic terminals. α-RIMs bind to Rab3 on synaptic vesicles and to Munc13 on the active zone via their N-terminal region, and interact with other synaptic proteins via their central and C-terminal regions. Although RIM1α has been well characterized, nothing is known about the function of RIM2α. We now show that RIM1α and RIM2α are expressed in overlapping but distinct patterns throughout the brain. To examine and compare their functions, we generated knockout mice lacking RIM2α, and crossed them with previously produced RIM1α knockout mice. We found that deletion of either RIM1α or RIM2α is not lethal, but ablation of both α-RIMs causes postnatal death. This lethality is not due to a loss of synapse structure or a developmental change, but to a defect in neurotransmitter release. Synapses without α-RIMs still contain active zones and release neurotransmitters, but are unable to mediate normal Ca ²⁺-triggered release. Our data thus demonstrate that α-RIMs are not essential for synapse formation or synaptic exocytosis, but are required for normal Ca²⁺-triggering of exocytosis.