Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3

Sakane, Ayuko; Manabe, Shoichi; Ishizaki, Hiroki; Tanaka-Okamoto, Miki; Kiyokage, Emi; Toida, Kazunori; Yoshida, Takayuki; Miyoshi, Jun; Kamiya, Haruyuki; Takai, Yoshimi; Sasaki, Takuya

doi:10.1073/pnas.0600304103

Cited by 85 publications

(94 citation statements)

References 35 publications

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“…Here we show, both with GDI and a protein cassette that binds Rab3A-GTP (46,99,100), that Rab3A activation relies on a novel signaling cascade involving cAMP/Epac (Fig. 8).…”

Section: Discussionmentioning

confidence: 61%

Epac Activates the Small G Proteins Rap1 and Rab3A to Achieve Exocytosis

Branham

Bustos

Blas

et al. 2009

Journal of Biological Chemistry

120

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Exocytosis of the acrosome (the acrosome reaction) relies on cAMP production, assembly of a proteinaceous fusion machinery, calcium influx from the extracellular medium, and mobilization from inositol 1,4,5-trisphosphate-sensitive intracellular stores. Addition of cAMP to human sperm suspensions bypasses some of these requirements and elicits exocytosis in a protein kinase A-and extracellular calcium-independent manner. The relevant cAMP target is Epac, a guanine nucleotide exchange factor for the small GTPase Rap. We show here that a soluble adenylyl cyclase synthesizes the cAMP required for the acrosome reaction. Epac stimulates the exchange of GDP for GTP on Rap1, upstream of a phospholipase C. The Epac-selective cAMP analogue 8-pCPT-2-O-Me-cAMP induces a phospholipase Cdependent calcium mobilization in human sperm suspensions. In addition, our studies identify a novel connection between cAMP and Rab3A, a secretory granule-associated protein, revealing that the latter functions downstream of soluble adenylyl cyclase/cAMP/Epac but not of Rap1. Challenging sperm with calcium or 8-pCPT-2-O-Me-cAMP boosts the exchange of GDP for GTP on Rab3A. Recombinant Epac does not release GDP from Rab3A in vitro, suggesting that the Rab3A-GEF activation by cAMP/Epac in vivo is indirect. We propose that Epac sits at a critical point during the exocytotic cascade after which the pathway splits into two limbs, one that assembles the fusion machinery into place and another that elicits intracellular calcium release.

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“…Here we show, both with GDI and a protein cassette that binds Rab3A-GTP (46,99,100), that Rab3A activation relies on a novel signaling cascade involving cAMP/Epac (Fig. 8).…”

Section: Discussionmentioning

confidence: 61%

Epac Activates the Small G Proteins Rap1 and Rab3A to Achieve Exocytosis

Branham

Bustos

Blas

et al. 2009

Journal of Biological Chemistry

120

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“…26,27 Here, we show that RAB3-GAP1/2 also affects intracellular protein aggregation and modulate autophagy at basal and rapamycin-induced conditions.…”

Section: Discussionmentioning

confidence: 70%

“…26,27 To investigate, whether the influence of the RAB3GAPs on autophagy is also mediated by this particular RAB protein, we analyzed the impact of RAB3 on autophagy. We detected the RAB3 isoforms A, B, C, and D in IMR-90 fibroblasts employing real-time PCR.…”

Section: Rab3gap1/2 Function During Autophagosome Formationmentioning

confidence: 99%

“…The catalytic subunit RAB3-GAP1 and the noncatalytic subunit RAB3GAP2 form the heterodimeric TBC domain-free RAB3GAP complex, 24,25 which has been linked to the regulation of the RAB GTPase RAB3 and exocytosis of hormones and neurotransmitters at the neuronal synapse. 26,27 Recently, RAB3GAP1 has been associated with LMAN1 (lectin, mannose-binding, 1), which functions in protein trafficking and indicates that the RAB3GAPs might actually be involved in additional trafficking processes. 28 Interestingly, mutations in RAB3GAP1 and RAB3GAP2 are known to cause the Warburg Micro and Martsolf Syndrome in humans, which are characterized by severe brain, eye, and endocrine abnormalities.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy

et al. 2014

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Abbreviations: ATG, autophagy-related; Bafi, bafilomycin A 1 ; BSA, bovine serum albumin; C. elegans, Caenorhabditis elegans; CAL-COCO2, calcium binding and coiled-coil domain 2; DAPI, 4', 6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide; DPH, 1, 6-diphenyl-1, 3, 5-hexatriene; eV, empty vector; FEZ, fasciculation and elongation protein zeta; GABARAP, GABA(A) receptor-associated protein; GEF, guanine nucleotide exchange factor; GFP, green fluorescent protein; MAP1LC3, microtubule-associated protein 1 light chain 3; NBR1, neighbor of BRCA1 gene 1; PE, phosphatidylethanolamine; PBS, phosphate-buffered saline; RABGAP, RAB GTPase activating protein; siRNA, small interfering RNA; SQSTM1, sequestosome 1; TBC domain, TRE2-BUB2-CDC16 domain.Macroautophagy is a degradative pathway that sequesters and transports cytosolic cargo in autophagosomes to lysosomes, and its deterioration affects intracellular proteostasis. Membrane dynamics accompanying autophagy are mostly elusive and depend on trafficking processes. RAB GTPase activating proteins (RABGAPs) are important factors for the coordination of cellular vesicle transport systems, and several TBC (TRE2-BUB2-CDC16) domain-containing RABGAPs are associated with autophagy. Employing C. elegans and human primary fibroblasts, we show that RAB3GAP1 and RAB3GAP2, which are components of the TBC domain-free RAB3GAP complex, influence protein aggregation and affect autophagy at basal and rapamycin-induced conditions. Correlating the activity of RAB3GAP1/2 with ATG3 and ATG16L1 and analyzing ATG5 punctate structures, we illustrate that the RAB3GAPs modulate autophagosomal biogenesis. Significant levels of RAB3GAP1/2 colocalize with members of the Atg8 family at lipid droplets, and their autophagy modulatory activity depends on the GTPase-activating activity of RAB3GAP1 but is independent of the RAB GTPase RAB3. Moreover, we analyzed RAB3GAP1/2 in relation to the previously reported suppressive autophagy modulators FEZ1 and FEZ2 and demonstrate that both reciprocally regulate autophagy. In conclusion, we identify RAB3GAP1/2 as novel conserved factors of the autophagy and proteostasis network.

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“…Rab3 for instance, has been shown to be regulated by Rab3 GAP, a protein involved in Warburg Micro syndrome, characterized by abnormal brain development and severe intellectual disability (Aligianis et al, 2005). In animal models, mutated Rab3 GAP has been shown to lead to accumulation of GTP-bound Rab3 and result in inhibition of glutamate release and altered short-term plasticity (Sakane et al, 2006).…”

Section: Genementioning

confidence: 99%