Redundant Functions of RIM1alpha and RIM2alpha in Ca(2+)-triggered Neurotransmitter Release

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2006 Nov 25

PMID 17124501

Citations 75

Authors

Susanne Schoch

Tobias Mittelstaedt

Pascal S Kaeser

Daniel Padgett

Nicole Feldmann

Vivien Chevaleyre

Pablo E Castillo

Robert E Hammer

Weiping Han

Frank Schmitz

Weichun Lin

Thomas C Sudhof

Affiliations

Soon will be listed here.

Abstract

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.

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References

Ohtsuka T, Takao-Rikitsu E, Inoue E, Inoue M, Takeuchi M, Matsubara K . Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1. J Cell Biol. 2002; 158(3):577-90. PMC: 2173811. DOI: 10.1083/jcb.200202083. View

Brandon E, Lin W, DAmour K, Pizzo D, Dominguez B, Sugiura Y . Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. J Neurosci. 2003; 23(2):539-49. PMC: 6741871. View

Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder J . Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A. 1993; 90(18):8424-8. PMC: 47369. DOI: 10.1073/pnas.90.18.8424. View

Koushika S, Richmond J, Hadwiger G, Weimer R, Jorgensen E, Nonet M . A post-docking role for active zone protein Rim. Nat Neurosci. 2001; 4(10):997-1005. PMC: 2585766. DOI: 10.1038/nn732. View

Laemmli U . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259):680-5. DOI: 10.1038/227680a0. View

Wang Y, Liu X, Biederer T, Sudhof T . A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones. Proc Natl Acad Sci U S A. 2002; 99(22):14464-9. PMC: 137906. DOI: 10.1073/pnas.182532999. View

Simsek-Duran F, Linden D, Lonart G . Adapter protein 14-3-3 is required for a presynaptic form of LTP in the cerebellum. Nat Neurosci. 2004; 7(12):1296-8. DOI: 10.1038/nn1348. View

OGorman S, Dagenais N, Qian M, Marchuk Y . Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. Proc Natl Acad Sci U S A. 1998; 94(26):14602-7. PMC: 25067. DOI: 10.1073/pnas.94.26.14602. View

Varoqueaux F, Sons M, Plomp J, Brose N . Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol Cell Biol. 2005; 25(14):5973-84. PMC: 1168806. DOI: 10.1128/MCB.25.14.5973-5984.2005. View

10.

Kaeser P, Sudhof T . RIM function in short- and long-term synaptic plasticity. Biochem Soc Trans. 2005; 33(Pt 6):1345-9. DOI: 10.1042/BST0331345. View

11.

Lonart G, Schoch S, Kaeser P, Larkin C, Sudhof T, Linden D . Phosphorylation of RIM1alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses. Cell. 2003; 115(1):49-60. DOI: 10.1016/s0092-8674(03)00727-x. View

12.

Johnson S, Halford S, Morris A, Patel R, Wilkie S, Hardcastle A . Genomic organisation and alternative splicing of human RIM1, a gene implicated in autosomal dominant cone-rod dystrophy (CORD7). Genomics. 2003; 81(3):304-14. DOI: 10.1016/s0888-7543(03)00010-7. View

13.

Andrews-Zwilling Y, Kawabe H, Reim K, Varoqueaux F, Brose N . Binding to Rab3A-interacting molecule RIM regulates the presynaptic recruitment of Munc13-1 and ubMunc13-2. J Biol Chem. 2006; 281(28):19720-31. DOI: 10.1074/jbc.M601421200. View

14.

Harris A, McCaig C . Motoneuron death and motor unit size during embryonic development of the rat. J Neurosci. 1984; 4(1):13-24. PMC: 6564761. View

15.

Rosenmund C, Sigler A, Augustin I, Reim K, Brose N, Rhee J . Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron. 2002; 33(3):411-24. DOI: 10.1016/s0896-6273(02)00568-8. View

16.

Rosahl T, Spillane D, Missler M, Herz J, Selig D, Wolff J . Essential functions of synapsins I and II in synaptic vesicle regulation. Nature. 1995; 375(6531):488-93. DOI: 10.1038/375488a0. View

17.

Takao-Rikitsu E, Mochida S, Inoue E, Deguchi-Tawarada M, Inoue M, Ohtsuka T . Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J Cell Biol. 2004; 164(2):301-11. PMC: 2172332. DOI: 10.1083/jcb.200307101. View

18.

Brose N, Hofmann K, Hata Y, Sudhof T . Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem. 1995; 270(42):25273-80. DOI: 10.1074/jbc.270.42.25273. View

19.

Powell C, Schoch S, Monteggia L, Barrot M, Matos M, Feldmann N . The presynaptic active zone protein RIM1alpha is critical for normal learning and memory. Neuron. 2004; 42(1):143-53. PMC: 3910111. DOI: 10.1016/s0896-6273(04)00146-1. View

20.

Sun L, Bittner M, Holz R . Rim, a component of the presynaptic active zone and modulator of exocytosis, binds 14-3-3 through its N terminus. J Biol Chem. 2003; 278(40):38301-9. DOI: 10.1074/jbc.M212801200. View