Redundant functions of RIM1[alpha] and RIM2[alpha] in Ca super(2+)-triggered neurotransmitter release

[alpha]-RIMs (RIM1[alpha] and RIM2[alpha]) are multidomain active zone proteins of presynaptic terminals. [alpha]-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 RIM1[alpha] has been well characterized, nothing is known about the function of RIM2[alpha]. We now show that RIM1[alpha] and RIM2[alpha] are expressed in overlapping but distinct patterns throughout the brain. To examine and compare their functions, we generated knockout mice lacking RIM2[alpha], and crossed them with previously produced RIM1[alpha] knockout mice. We found that deletion of either RIM1[alpha] or RIM2[alpha] is not lethal, but ablation of both [alpha]-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 [alpha]-RIMs still contain active zones and release neurotransmitters, but are unable to mediate normal Ca super(2+)-triggered release. Our data thus demonstrate that [alpha]-RIMs are not essential for synapse formation or synaptic exocytosis, but are required for normal Ca super(2+)- triggering of exocytosis.