HGNC Approved Gene Symbol: RAB3A
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:18,196,784-18,204,042 (from NCBI)
The RAS gene superfamily is divided into 3 main branches according to protein homology. In mammals the first branch includes the classic RAS genes as well as RAL (179550) and RRAS (165090). The RHO genes (165370, 165380, 165390) belong to the second branch and the RAB genes to the third. The RAB genes were so named because they were first isolated from a rat brain library. Zahraoui et al. (1989) isolated cDNAs encoding RAB3A and several other human RAB proteins. See RAB5A (179512). The predicted 220-amino acid human RAB3A protein shares 99% and 78% identity with rat Rab3A and human RAB3B (179510), respectively.
Using yeast 2-hybrid analysis and in vitro binding assays, Martincic et al. (1997) showed that rat Pra1 (RABAC1; 604925) bound prenylated Rab GTPases, including Rab3a and Rab1 (179508), but not other small Ras-like GTPases. Pra1 also interacted with the synaptic vesicle protein Vamp2 (185881), but not Vamp1 (185880) or cellubrevin (VAMP3; 603657). Deletion analysis showed that both an N-terminal region spanning amino acids 30 to 54 and the extreme C-terminal domain of Pra1 were required for binding both Rab GTPases and Vamp1. Martincic et al. (1997) suggested that PRA1 may link Rab proteins and VAMP2 in the control of vesicle docking and fusion.
Giovedi et al. (2004) found that interaction between mammalian synapsin I (SYN1; 313440) and Rab3a regulated the activities of both proteins. Synapsin I stimulated the Rab3a cycle by increasing GTP binding, GTPase activity, and Rab3a recruitment to the synaptic vesicle membrane. Conversely, Rab3a inhibited synapsin I binding to actin and synapsin I-induced synaptic vesicle clustering.
Corticoamygdala long-term potentiation (LTP) and late-phase LTP at hippocampal synapses are 2 forms of LTP that require both postsynaptic NMDA receptor (see, e.g., 138249) activation and presynaptic protein kinase A (PKA; see 176911) activation. By in vitro analysis of transverse slices from the hippocampus and lateral amygdala of Rab3a-null mice, Huang et al. (2005) found that Rab3a was necessary for both forms of synaptic plasticity. Rim1-alpha (606629), a Rab3a-interacting molecule, was also required for hippocampal late-phase LTP. The findings indicated that presynaptic proteins also play a role in plasticity that is dependent on postsynaptic activity, thus adding a layer of complexity to synaptic interactions.
Ruediger et al. (2011) investigated how mossy fiber terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and the functional role of the rearrangements. Ruediger et al. (2011) showed that one-trial and incremental learning lead to robust, circuit-specific, long-lasting, and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the number of c-Fos (164810)-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. Ruediger et al. (2011) then showed that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibers has a critical role for the precision of the memory and the learned behavior. In the absence of mossy fiber long-term potentiation in Rab3a-null mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin-2 (ADD2; 102681), c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibers. Ruediger et al. (2011) concluded that their results established a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further related plasticity and feedforward inhibition growth at hippocampal mossy fibers to the precision of hippocampus-dependent memories.
Sullivan et al. (1999) found that the RAB3A gene consists of 5 exons spanning 7.9 kb, and is located 3.7 kb from PDE4C (600128).
Rousseau-Merck et al. (1989, 1989) used the cloned human RAB3A cDNA as a probe to map the corresponding gene by hybridization to flow sorted chromosomes and by in situ hybridization. They concluded that RAB3A is located on 19p13.2. The RAB genes may serve a regulatory function in the developing nervous system. No oncogenic activity has been demonstrated as yet for any of the RAB branch family genes. It is noteworthy, however, that the 19p13.2 site is involved in malignant processes such as acute leukemias. By fluorescence in situ hybridization, Trask et al. (1993) assigned the RAB3A gene to 19p13.1-p12.
In brain, RAB3A is found specifically in synaptic vesicles. Geppert et al. (1997) generated Rab3a-deficient mice. They found that the size of the readily releasable pool of vesicles was normal, but that calcium-triggered fusion was altered in the absence of Rab3a such that a greater number of exocytic events occurred within a brief time after arrival of the nerve impulse. They concluded that RAB3A regulates a late step in synaptic vesicle fusion.
Kapfhamer et al. (2002) identified a semidominant mouse mutation called 'earlybird' (Ebd) that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (asp77 to gly) within the GTP-binding domain of the Rab3a protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors.
Geppert, M., Goda, Y., Stevens, C. F., Sudhof, T. C. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature 387: 810-814, 1997. [PubMed: 9194562] [Full Text: https://doi.org/10.1038/42954]
Giovedi, S., Darchen, F., Valtorta, F., Greengard, P., Benfenati, F. Synapsin is a novel Rab3 effector protein on small synaptic vesicles. II. Functional effects of the Rab3A-synapsin I interaction. J. Biol. Chem. 279: 43769-43779, 2004. [PubMed: 15265868] [Full Text: https://doi.org/10.1074/jbc.M404168200]
Huang, Y.-Y., Zakharenko, S. S., Schoch, S., Kaeser, P. S., Janz, R., Sudhof, T. C., Siegelbaum, S. A., Kandel, E. R. Genetic evidence for a protein-kinase-A-mediated presynaptic component in NMDA-receptor-dependent forms of long-term synaptic potentiation. Proc. Nat. Acad. Sci. 102: 9365-9370, 2005. [PubMed: 15967982] [Full Text: https://doi.org/10.1073/pnas.0503777102]
Kapfhamer, D., Valladares, O., Sun, Y., Nolan, P. M., Rux, J. J., Arnold, S. E., Veasey, S. C., Bucan, M. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nature Genet. 32: 290-295, 2002. [PubMed: 12244319] [Full Text: https://doi.org/10.1038/ng991]
Martincic, I., Peralta, M. E., Ngsee, J. K. Isolation and characterization of a dual prenylated Rab and VAMP2 receptor. J. Biol. Chem. 272: 26991-26998, 1997. [PubMed: 9341137] [Full Text: https://doi.org/10.1074/jbc.272.43.26991]
Rousseau-Merck, M. F., Zahraoui, A., Bernheim, A., Touchot, N., Miglierina, R., Tavitian, A., Berger, R. Chromosome mapping of the human RAS related RAB3A and RAB3B genes to chromosomes 19p13.2 and 1p31-p32, respectively. (Abstract) Cytogenet. Cell Genet. 51: 1070 only, 1989.
Rousseau-Merck, M. F., Zahraoui, A., Bernheim, A., Touchot, N., Miglierina, R., Tavitian, A., Berger, R. Chromosome mapping of the human RAS-related RAB3A gene to 19p13.2. Genomics 5: 694-698, 1989. [PubMed: 2687157] [Full Text: https://doi.org/10.1016/0888-7543(89)90110-9]
Ruediger, S., Vittori, C., Bednarek, E., Genoud, C., Strata, P., Sacchetti, B., Caroni, P. Learning-related feedforward inhibitory connectivity growth required for memory precision. Nature 473: 514-518, 2011. [PubMed: 21532590] [Full Text: https://doi.org/10.1038/nature09946]
Sullivan, M., Olsen, A. S., Houslay, M. D. Genomic organisation of the human cyclic AMP-specific phosphodiesterase PDE4C gene and its chromosomal localisation to 19p13.1, between RAB3A and JUND. Cell. Signal. 11: 735-742, 1999. [PubMed: 10574328] [Full Text: https://doi.org/10.1016/s0898-6568(99)00037-6]
Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15: 133-145, 1993. [PubMed: 8432525] [Full Text: https://doi.org/10.1006/geno.1993.1021]
Zahraoui, A., Touchot, N., Chardin, P., Tavitian, A. The human rab genes encode a family of GTP-binding proteins related to yeast YPT1 and SEC4 products involved in secretion. J. Biol. Chem. 264: 12394-12401, 1989. [PubMed: 2501306]