Redundant functions of RIM1alpha and RIM2alpha in Ca(2+)-triggered neurotransmitter release.
Alpha-RIMs (RIM1alpha and RIM2alpha) 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 RIM1alpha has been well characterized, nothing is known about the function of RIM2alpha. We now show that RIM1alpha and RIM2alpha are expressed in overlapping but distinct patterns throughout the brain. To examine and compare their functions, we generated knockout mice lacking RIM2alpha, and crossed them with previously produced RIM1alpha knockout mice. We found that deletion of either RIM1alpha or RIM2alpha 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(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(2+)-triggering of exocytosis.
Schoch
Susanne
S
Emmy Noether Research Group, Institute of Neuropathology, Department of Epileptology, University Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany. susanne.schoch@uni-bonn.de
Mittelstaedt
Tobias
T
Kaeser
Pascal S
PS
Padgett
Daniel
D
Feldmann
Nicole
N
Chevaleyre
Vivien
V
Castillo
Pablo E
PE
Hammer
Robert E
RE
Han
Weiping
W
Schmitz
Frank
F
Lin
Weichun
W
Südhof
Thomas C
TC
D000200:Action Potentials; D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology; D002118:Calcium / Q000378:metabolism*; D004594:Electrophysiology; D004622:Embryo, Mammalian / Q000166:cytology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006579:Heterozygote; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000166:cytology / Q000648:ultrastructure; D018377:Neurotransmitter Agents / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000166:cytology / Q000648:ultrastructure; D016019:Survival Analysis; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism*
D007328:Insulin; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; C491490:Rims1 protein, mouse; C491489:Rims1 protein, rat; C484282:Rims2 protein, rat; D019204:GTP-Binding Proteins; C475524:Rim2 protein, mouse; D020692:rab3 GTP-Binding Proteins; D002118:Calcium