Synaptic targeting of rabphilin-3A, a synaptic vesicle Ca2+/phospholipid-binding protein, depends on rab3A/3C

Li, Cai; Takei, Kohji; Geppert, Martin; Daniell, Laurie; Stenius, Katinka; Chapman, Edwin R.; Jahn, Reinhard; Camilli, Pietro De; Südhof, Thomas C.

doi:10.1016/0896-6273(94)90254-2

Cited by 192 publications

(183 citation statements)

References 39 publications

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“…It is now clear that rab3 interacts with a series of proteins. Among them, rabphilin3A, originally described as a synaptic vesicle protein and recently identified in hormone secreting cells from various species [40], has been found to interact with rab3a and rab3c in a GTP-dependent manner [41,42]. The widely expressed protein rabin3 interacts with rab3a and rab3d (but not with rab3c) [43], whereas SNAP-25, VAMP/synaptobrevin-2, and syntaxins have been found to exist as a complex with rab3a in brain presynaptic terminals [44].…”

Section: Discussionmentioning

confidence: 99%

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A₂ metabolites

Garde

Roldán

1996

FEBS Letters

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Aerosomal exocytosis triggered with A23187/Ca 2+ was enhanced by rab3AL, a synthetic peptide corresponding to the effector domain of the small GTP-binding protein rab3. Exocytosis was further enhanced when spermatozoa were also exposed to dihutyryl-cAMP, but was prevented when H-89, a protein kinase A (PKA) inhibitor, was included. The action of rab3AL was not on, or upstream of, phospholipase A2 (PLA2). Inhibition of exocytosis by the PLA2 inhibitor aristolochic acid was overcome by rab3AL when it was included together with lysophosphatidylcholine; this effect was prevented by H-89. These results suggest a functional coupling between rab3 protein, metabolites generated by PLA2, and cAMP-activated PKA, in the final steps leading to membrane fusion during acrosomal exocytosis.Key words: Exocytosis; rab3; Phospholipase Az; Lysophosphatidylcholine; cAMP; Spermatozoa that regulate docking and fusion of secretory granules with the plasma membrane [16][17][18][19].Synthetic peptides corresponding to a putative effector domain of rab3 proteins have been shown to stimulate exocytosis in permeabilized [20 23] and intact cells [24], and membrane fusion in a cell-free assay system [25]. We have therefore used a sperm model system, where cells are stimulated to undergo exocytosis with A23187/Ca 2+, to explore whether rab3 might be involved in the final steps of membrane fusion during acrosomal exocytosis. We present, for the first time, evidence suggesting that rab3 protein, together with PLA2-derived metabolites and the cAMP/PKA signalling pathway, play an important role during the final steps of acrosomal exocytosis in mammalian spermatozoa. Materials and methods

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Section: Discussionmentioning

confidence: 99%

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A₂ metabolites

Garde

Roldán

1996

FEBS Letters

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“…In vertebrates, rabphilin was originally identified as a Rab3 effector (Shirataki et al, 1993;Li et al, 1994;Ostermeier and Brunger, 1999); however, this does not seem to be the case in C. elegans (Staunton et al, 2001). Similarly, studies in mice have shown that rabphilin is not required for Rab3 function (Schluter et al, 1999).…”

Section: Rab-27 Regulates Rbf-1mentioning

confidence: 99%

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Mahoney

Liu

Itoh

et al. 2006

MBoC

164

218

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Rab small GTPases are involved in the transport of vesicles between different membranous organelles. RAB-3 is an exocytic Rab that plays a modulatory role in synaptic transmission. Unexpectedly, mutations in the Caenorhabditis elegans RAB-3 exchange factor homologue, aex-3, cause a more severe synaptic transmission defect as well as a defecation defect not seen in rab-3 mutants. We hypothesized that AEX-3 may regulate a second Rab that regulates these processes with RAB-3. We found that AEX-3 regulates another exocytic Rab, RAB-27. Here, we show that C. elegans RAB-27 is localized to synapse-rich regions pan-neuronally and is also expressed in intestinal cells. We identify aex-6 alleles as containing mutations in rab-27. Interestingly, aex-6 mutants exhibit the same defecation defect as aex-3 mutants. aex-6; rab-3 double mutants have behavioral and pharmacological defects similar to aex-3 mutants. In addition, we demonstrate that RBF-1 (rabphilin) is an effector of RAB-27. Therefore, our work demonstrates that AEX-3 regulates both RAB-3 and RAB-27, that both RAB-3 and RAB-27 regulate synaptic transmission, and that RAB-27 potentially acts through its effector RBF-1 to promote soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) function. INTRODUCTIONNeurotransmitter release is accomplished by the fusion of neurotransmitter-filled synaptic vesicles at the presynaptic nerve terminal. This process occurs through a series of highly regulated steps that include synaptic vesicle transport, docking/tethering, priming, fusion, endocytosis, recycling, and neurotransmitter refilling (Sudhof, 2004). Several genes have been assigned roles in the various steps of the synaptic vesicle cycle. Rab3 (termed RAB-3 in Caenorhabditis elegans), a member of the Rab family of small GTPases, regulates synaptic transmission, possibly through the docking, priming, or fusion steps Schluter et al., 2004).Rabs act in a variety of cell types and regulate vesicular transport between organelles. Rabs cycle on and off membranes via a GTP-dependent mechanism (Zerial and McBride, 2001). Rab activity is regulated by two proteins, which act in an antagonistic manner. The guanine nucleotide exchange factor (GEF) exchanges GTP for GDP, and the GTPase activating protein activates the intrinsic GTPase activity of a Rab (Bernards, 2003). GDP bound Rabs are held off of the membrane by a GDP dissociation inhibitor (Wu et al., 1996). The GTP/membrane-bound form of Rabs typically binds to a variety of effectors that regulate particular steps of membrane transport and cell signaling (Zerial and McBride, 2001;Spang, 2004).Rab3 was once thought to play a central role in regulating release. However, recent work has shown that a quadruple knockout of all four isoforms of Rab3 in mice only results in a 30% reduction in evoked synaptic response (Schluter et al., 2004). This is consistent with work in C. elegans showing that mutations in the single rab-3 gene cause only mild defects in synaptic transmission . Surprisingly, more dramatic phe...

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Section: Introductionmentioning

confidence: 99%

“…Rabphilin3 colocalizes with Rab3A, its counterpart on synaptic vesicles in axon terminals (Shirataki et al 1994;Li et al 1994). The 4 localization of rabphilin3 is thought to be dependent on Rab3A (Li et al 1994) although recent studies suggest a more specific interaction of rabphilin3 with Rab27A (Fukuda 2003;Fukuda et al 2004). Rab3A is shared by neurons and endocrine cells, while rabphilin3 is expressed exclusively in neurons and neuron-like cells (adrenal chromaffin cells), and is absent or present only at very low levels in endocrine cells (Inagaki et al 1994;Regazzi et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Cellular expression of Noc2, a Rab effector protein, in endocrine and exocrine tissues in the mouse

Teramae

Fujimoto

Seino

et al. 2006

Histochem Cell Biol

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Noc2 is a Rab effector which participates in regulated exocytosis. It is expressed abundantly in endocrine cells but at low levels in exocrine tissues. Noc2-deficient mice, however, exhibit marked accumulation of secretory granules in exocrine cells rather than endocrine cells. In the present study, we investigated localization of Noc2 immunohistochemically in various endocrine and exocrine tissues in normal mice.Western blotting detected a Noc2-immunoreactive band of 38 kDa in isolated pancreatic islets, the adrenal gland, pituitary gland, and thyroid gland. Immunostaining for Noc2 labeled endocrine cells in the adrenal medulla and adenohypophysis, pancreatic islet cells, thyroid parafollicular cells, and gut endocrine cells, supporting the notion that Noc2 is a Rab effector protein shared by amine/peptide-secreting endocrine cells.

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Synaptic targeting of rabphilin-3A, a synaptic vesicle Ca2+/phospholipid-binding protein, depends on rab3A/3C

Cited by 192 publications

References 39 publications

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A₂ metabolites

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A₂ metabolites

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Cellular expression of Noc2, a Rab effector protein, in endocrine and exocrine tissues in the mouse

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Synaptic targeting of rabphilin-3A, a synaptic vesicle Ca2+/phospholipid-binding protein, depends on rab3A/3C

Cited by 192 publications

References 39 publications

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A2 metabolites

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A2 metabolites

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Cellular expression of Noc2, a Rab effector protein, in endocrine and exocrine tissues in the mouse

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rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A₂ metabolites

rab3‐Peptide stimulates exocytosis of the ram sperm acrosome via interaction with cyclic AMP and phospholipase A₂ metabolites