Rab27b is associated with fusiform vesicles and may be involved in targeting uroplakins to urothelial apical membranes

Chen, Yanru; Guo, Xuemei; Deng, Fang−Ming; Liang, Feng; Sun, Wenyu; Ren, Mindong; Izumi, Tetsuro; Sabatini, David D.; Sun, Tung‐Tien; Kreibich, Gert

doi:10.1073/pnas.2436350100

Cited by 69 publications

(78 citation statements)

References 57 publications

(62 reference statements)

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“…The immunodeficiency of Griscelli syndrome patients is due to a defect in lytic granule exocytosis from cytotoxic T-cells and may be mediated by effectors such as Munc13-4 and granuphilin Goishi et al, 2004;Shirakawa et al, 2004;Torii et al, 2004;Yamamoto et al, 2004;Neeft et al, 2005). In addition, Rab27 plays a role in exocytosis of dense core granules from both endocrine and exocrine cells (Chen et al, 2003;Fukuda, 2003b;Izumi et al, 2003;Chen et al, 2004;Goishi et al, 2004;Imai et al, 2004;Matsumoto et al, 2004). Until now, the role of Rab27 in the nervous system was unknown.…”

Section: Discussionmentioning

confidence: 99%

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

Mahoney

Liu

Itoh

et al. 2006

MBoC

155

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: Discussionmentioning

confidence: 99%

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

Mahoney

Liu

Itoh

et al. 2006

MBoC

155

218

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“…An open question is why both Rab11a and Rab27b are present on DFV (8). One possibility is that these GTPases function in a sequential fashion to regulate DFV maturation and exocytosis.…”

Section: Discussionmentioning

confidence: 99%

Rab11a-dependent exocytosis of discoidal/fusiform vesicles in bladder umbrella cells

Khandelwal¹,

Ruiz²,

Hawryluk

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

112

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The discoidal/fusiform vesicles (DFV) of bladder umbrella cells undergo regulated exocytosis in response to stretch, but little is known about their biogenesis or the molecular machinery that modulates this process. We observed that Rab11a was expressed in umbrella cells (but not Rab11b or Rab25) and was associated with DFV. Using adenovirus-mediated delivery we transduced umbrella cells in situ with either dominant active (DA) or dominant negative (DN) mutants of Rab11a. DA-Rab11a stimulated an increase in apical surface area in the absence of stretch, whereas DN-Rab11a inhibited stretch-induced changes. Endocytosed fluid and membrane markers had little access to Rab11a-positive DFV, but virally expressed human growth hormone (hGH), a secretory protein, was packaged into DFV. Whereas expression of DARab11a stimulated release of hGH into the bladder lumen, expression of DN-Rab11a had the opposite effect. Our results indicate that DFV may be biosynthetic in nature and that their exocytosis depends on the activity of the Rab11a GTPase.uroepithelium ͉ urothelium ͉ GTPases

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“…Previous studies implicated the cytoskeleton, ATP (as an intracellular energy source), cAMP, Ca 2+ signaling cascades, and possibly Rab27b and SNARE fusion components in discoidal/fusiform vesicle exocytosis (26,28,(56)(57)(58). However, a proximal signal(s) for exocytosis has yet to be described.…”

Section: Discussionmentioning

confidence: 99%

ATP and purinergic receptor–dependent membrane traffic in bladder umbrella cells

Wang¹,

Lee²,

Ruiz³

et al. 2005

J. Clin. Invest.

205

223

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The umbrella cells that line the bladder are mechanosensitive, and bladder filling increases the apical surface area of these cells; however, the upstream signals that regulate this process are unknown. Increased pressure stimulated ATP release from the isolated uroepithelium of rabbit bladders, which was blocked by inhibitors of vesicular transport, connexin hemichannels, ABC protein family members, and nucleoside transporters. Pressure-induced increases in membrane capacitance (a measure of apical plasma membrane surface area where 1 µF ≈ 1 cm 2 ) were inhibited by the serosal, but not mucosal, addition of apyrase or the purinergic receptor antagonist PPADS. Upon addition of purinergic receptor agonists, increased capacitance was observed even in the absence of pressure. Moreover, knockout mice lacking expression of P2X 2 and/or P2X 3 receptors failed to show increases in apical surface area when exposed to hydrostatic pressure. Treatments that prevented release of Ca 2+ from intracellular stores or activation of PKA blocked ATPγS-stimulated changes in capacitance. These results indicate that increased hydrostatic pressure stimulates release of ATP from the uroepithelium and that upon binding to P2X and possibly P2Y receptors on the umbrella cell, downstream Ca 2+ and PKA second messenger cascades may act to stimulate membrane insertion at the apical pole of these cells.

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Rab27b is associated with fusiform vesicles and may be involved in targeting uroplakins to urothelial apical membranes

Cited by 69 publications

References 57 publications

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

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

Rab11a-dependent exocytosis of discoidal/fusiform vesicles in bladder umbrella cells

ATP and purinergic receptor–dependent membrane traffic in bladder umbrella cells

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