Regulation of Membrane Transport by rab GTPases

Deneka, Magdalena; Neeft, Maaike; Sluijs, Peter van der

doi:10.1080/713609214

Cited by 122 publications

(89 citation statements)

References 169 publications

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“…The PIM contained 5 g/ml pepstatin, 50 g/ml leupeptin, and 5 g/ml aprotinin and was included with each lysis buffer (31). Samples were analyzed by SDS-PAGE and transferred to nitrocellulose.…”

Section: Methodsmentioning

confidence: 99%

“…In adipocytes, Rab4 controls recycling of the insulin-regulated glucose transporter GLUT4 (37), and recombinant Rab4 stimulates ␣-granule secretion in platelets in vitro (38). All Rab proteins contain highly conserved domains required for guanine nucleotide binding, GTP/GDP exchange, and GTP hydrolysis that are essential for their proper targeting and function (31).…”

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confidence: 99%

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Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Ahmed

Jeffus

Bukhari

et al. 2008

Journal of Biological Chemistry

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The serotonin transporter (SERT) on the plasma membrane is the major mechanism for the clearance of plasma serotonin (5-hydroxytryptamine (5HT)). The uptake rates of cells depend on the density of SERT molecules on the plasma membrane. Interestingly, the number of SERT molecules on the platelet surface is down-regulated when plasma 5HT ([5HT] ex ) is elevated. It is well reported that stimulation of cells with high [5HT] ex induces transamidation of a small GTPase, Rab4. Modification with 5HT stabilizes Rab4 in its active, GTP-bound form, Rab4-GTP. Although investigating the mechanism by which elevated plasma 5HT level down-regulates the density of SERT molecules on the plasma membrane, we studied Rab4 and SERT in heterologous and platelet expression systems. Our data demonstrate that, in response to elevated [5HT] ex , Rab4-GTP co-localizes with and binds to SERT. The association of SERT with Rab4-GTP depends on: (i) 5HT modification and (ii) the GTP-binding ability of Rab4. Their association retains transporter molecules intracellularly. Furthermore, we mapped the Rab4-SERT association domain to amino acids 616 -624 in the cytoplasmic tail of SERT. This finding provides an explanation for the role of the C terminus in the localization and trafficking of SERT via Rab4 in a plasma 5HT-dependent manner. Therefore, we propose that elevated [5HT] ex "paralyzes" the translocation of SERT from intracellular locations to the plasma membrane by controlling transamidation and Rab4-GTP formation.The serotonin transporter (SERT) 2 is a member of the Cl Ϫ -and Na ϩ -dependent monoamine transporter family, which also includes the dopamine transporter (DAT) and the norepinephrine transporter. SERT is a 630-amino acid plasma membrane-bound glycoprotein. Hydropathy analysis predicts that SERT contains 12 transmembrane domains and that both the N and C termini are exposed to the cytoplasm. The primary function of SERT in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin (5-hydroxytryptamine (5HT)) molecules from the synaptic cleft into the pre-synaptic terminal for re-utilization. SERT is also expressed in non-neuronal cells, including platelets, placental, intestinal and adrenal cell lines, but the exact function of SERT in these cell lines is still under investigation (1-5).The C-and N-terminal regions of monoamine transporter proteins have just recently garnered increased attention for their importance in transport function and localization. Significant work has been accomplished in identifying the importance of the C-terminal region of DAT and norepinephrine transporter in transporter function, expression, and localization (6 -9).The proteins interacting with the N terminus of SERT are syntaxin 1A (10, 11) and secretory carrier membrane protein 2 (12). SERT also complexes with Hic-5 (13) and ␣-synuclein (14), but the functional significance of these interactions are not known. PICK1 (15), MacMARCKS (16), the actin cytoskeleton (49), neuronal nitric-oxide synthase, and Se...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Ahmed

Jeffus

Bukhari

et al. 2008

Journal of Biological Chemistry

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“…In the case of epithelial cells, this includes sorting of proteins to either the apical or basolateral surface of the plasma membrane. The processes by which proteins are sorted into transport vesicles and vesicles are formed, transported, and fused with specific target compartments is mediated by the concerted actions of monomeric Rab proteins, SNARE (soluble n-ethyl-maleimide-sensitive factor attachment protein receptor) proteins and their effectors (Rodman and Wandinger-Ness, 2000;Deneka et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Rab10 Regulates Membrane Transport through Early Endosomes of Polarized Madin-Darby Canine Kidney Cells

Babbey

Ahktar

Wang

et al. 2006

MBoC

155

129

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“…Rabs, which cycle between GTPbound active states and GDP-bound inactive states as assisted by guanine nucleotide exchange factors or GTPase activating proteins, respectively, are implicated in protein trafficking and targeting and fusion of membranous organelles in all eukaryotic cell types (11,12,40). In acinar cells from the LG, pancreas, and parotid gland, the Rab3D isoform is enriched on mature SV and appears to serve as a negative regulator of homotypic fusion (38).…”

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confidence: 99%

Rab27b regulates exocytosis of secretory vesicles in acinar epithelial cells from the lacrimal gland

Chiang¹,

Ngo²,

Schechter

et al. 2011

American Journal of Physiology-Cell Physiology

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mechanisms largely yet uncharacterized. We investigated the role of Rab27b in the terminal release of these secretory vesicles. Confocal fluorescence microscopy analysis of primary cultured rabbit lacrimal gland acinar cells revealed that Rab27b was enriched on the membrane of large subapical vesicles that were significantly colocalized with Rab3D and Myosin 5C. Stimulation of cultured acinar cells with the secretagogue carbachol resulted in apical fusion of these secretory vesicles with the plasma membrane. Evaluation of morphological changes by transmission electron microscopy of lacrimal glands from Rab27b Ϫ/Ϫ and Rab27 ash/ash /Rab27b Ϫ/Ϫ mice, but not ashen mice deficient in Rab27a, showed changes in abundance and organization of secretory vesicles, further confirming a role for this protein in secretory vesicle exocytosis. Glands lacking Rab27b also showed increased lysosomes, damaged mitochondria, and autophagosomelike organelles. In vitro, expression of constitutively active Rab27b increased the average size but retained the subapical distribution of Rab27b-enriched secretory vesicles, whereas dominant-negative Rab27b redistributed this protein from membrane to the cytoplasm. Functional studies measuring release of a cotransduced secretory protein, syncollin-GFP, showed that constitutively active Rab27b enhanced, whereas dominant-negative Rab27b suppressed, stimulated release. Disruption of actin filaments inhibited vesicle fusion to the apical membrane but did not disrupt homotypic fusion. These data show that Rab27b participates in aspects of lacrimal gland acinar cell secretory vesicle formation and release. actin; Rab3d; exocrine secretion; syncollin; mouse models A FUNCTIONING LACRIMAL GLAND (LG) is critical for a healthy ocular surface. This exocrine gland is the primary source of tear proteins and fluid, which, released up on the gland's exposure to sympathetic or parasympathetic agonists provided by innervating nerves, contribute to the middle aqueous layer of the precorneal film. Much of the LG's secretions originate from acinar cells, which constitute over 80% of the mass of the LG (13). These LG acinar cells produce a diverse array of secretory proteins that are internally sorted into large pools of serous and mucous secretory vesicles (SV) sized ϳ1 m in diameter and stored beneath the apical plasma membrane (APM) in preparation for regulated exocytosis. SV contents include nutrients and growth factors (lacritin and EGF), antibacterial and antiviral factors (secretory IgA and lactoferrin), and an array of proteases and lysosomal hydrolases (10, 39, 47). Despite its physiological importance, however, few studies have focused on the mechanisms of secretory membrane trafficking in LG acinar cells, in part due to the fragility and heterogeneity of these LG acinar SV relative to those in other acinar secretory cells, e.g., pancreatic acini (7).The current schematic of exocytosis in the LG acinar cell suggests multiple participants. Mature LG acinar cell SV localize beneath an actin-rich network und...

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Regulation of Membrane Transport by rab GTPases

Cited by 122 publications

References 169 publications

Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Serotonin Transamidates Rab4 and Facilitates Its Binding to the C Terminus of Serotonin Transporter

Rab10 Regulates Membrane Transport through Early Endosomes of Polarized Madin-Darby Canine Kidney Cells

Rab27b regulates exocytosis of secretory vesicles in acinar epithelial cells from the lacrimal gland

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