Regulated Exocytosis in Chromaffin Cells

Galas, Marie‐Christine; Helms, J. Bernd; Vitale, Nicolas; Thiersé, Danièle; Aunis, Dominique; Bader, Marie‐France

doi:10.1074/jbc.272.5.2788

Cited by 124 publications

(74 citation statements)

References 42 publications

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“…4 A-C). Desensitization of LH͞CGR activity was more sensitive to inhibition by the MyrArf6 peptide compared with non-Myr-Arf6, consistent with their relative activity in intact cells (38). Higher concentrations of both Myr-Arf6 and -Arf1 peptides, but not the non-Myr-Arf6 peptide, reduced hCG-and forskolin-stimulated AC activities in a 5-min AC assay, suggesting that Myr-Arf peptides interfered directly with AC activation (data not shown).…”

Section: Resultssupporting

confidence: 58%

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The ADP ribosylation factor nucleotide exchange factor ARNO promotes β-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization

Mukherjee

Gurevich

Jones

et al. 2000

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

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Desensitization of guanine nucleotide binding protein-coupled receptors is a ubiquitous phenomenon characterized by declining effector activity upon persistent agonist stimulation. The luteinizing hormone/choriogonadotropin receptor (LH/CGR) in ovarian follicles exhibits desensitization of effector adenylyl cyclase activity in response to the mid-cycle surge of LH. We have previously shown that uncoupling of the agonist-activated LH/CGR from the stimulatory G protein (G s) is dependent on GTP and attributable to binding of ␤-arrestin present in adenylyl cyclase-rich follicular membrane fraction to the third intracellular (3i) loop of the receptor. Here, we report that LH/CGR-dependent desensitization is mimicked by ADP ribosylation factor nucleotide-binding site opener, a guanine nucleotide exchange factor of the small G proteins ADP ribosylation factors (Arfs) 1 and 6, and blocked by synthetic N-terminal Arf6 peptide, suggesting that the GTP-dependent step of LH/CGR desensitization is receptor-dependent Arf6 activation. Arf activation by GTP and ADP ribosylation factor nucelotide-binding site opener promotes the release of docked ␤-arrestin from the membrane, making ␤-arrestin available for LH/CGR; Arf6 but not Arf1 peptides block ␤-arrestin release from the membrane. Thus, LH/CGR appears to activate two membrane delimited signaling cascades via two types of G proteins: heterotrimeric Gs and small G protein Arf6. Arf6 activation releases docked ␤-arrestin necessary for receptor desensitization, providing a feedback mechanism for receptor self-regulation.T he luteinizing hormone/choriogonadotropin receptor (LH/ CGR) belongs to the seven transmembrane family of receptors that signal by the activation of guanine nucleotide binding (G) proteins and downstream effectors including adenylyl cyclase (AC) (1-4). Characteristic of virtually all G proteincoupled receptors (GPCRs) (5), LH-and human (h) CG-stimulated AC activities wane in response to persistent stimulation of the LH/CGR by saturating agonist concentrations (6-8). We have previously shown that desensitization of the endogenous ovarian follicular LH/CGR in a cell-free membrane model is GTP dependent (K m Ϸ70 nM) (9-11). Based on the ability of anti-arrestin antibodies to abrogate LH/CGR desensitization, we concluded that endogenous plasma membranebound ␤-arrestin mediates desensitization of the follicular LH/ CGR (12). Using synthetic peptides, we have also shown that on LH/CGR activation, ␤-arrestin specifically binds to the 3i loop of the activated LH/CGR, blocking its interaction with G s (13). Here, we investigate the molecular basis of the GTP dependence of LH/CGR desensitization and the mechanism of the release of the membrane-bound ␤-arrestin required for LH/CGR desensitization. Materials and MethodsMaterials. , ADP ribosylation factor (Arf) nucleotide-binding site opener (ARNO) and ARNO mutant proteins (15), and Clostridium difficile and Clostridium sordelli toxins (16) were expressed and purified as described. Myristoylated (Myr)-Arf6(2-13), non-Myr-...

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Section: Resultssupporting

confidence: 58%

“…GLUT4 translocation (41), to participate in regulated exocytosis by activating phospholipase D (17,38), to play a regulatory role in receptor-mediated endocytosis (39), to remodel the actin cytoskeleton (34,42), and to be required for phagocytosis in macrophage (43). Our results show that Arf6 also participates in GPCR desensitization.…”

Section: Discussionmentioning

confidence: 61%

The ADP ribosylation factor nucleotide exchange factor ARNO promotes β-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization

Mukherjee

Gurevich

Jones

et al. 2000

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

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“…Several lines of evidence also support a unique role for ARF6 in regulating cortical actin structure and function (44,45). In view of the convergence in molecules and mechanisms underlying the multiple steps of intracellular vesicular transport, we previously investigated the possible function of members of the ARF family in calciumregulated exocytosis (11,23). Our findings suggested that a granule-bound ARF6 plays a direct role in the late stages of exocytosis, most likely by stimulating a PLD activity located at the plasma membrane.…”

Section: -1921mentioning

confidence: 99%

“…We recently described the presence of a secretory granuleassociated ARF6 protein in adrenal medullary chromaffin cells (11). Secretagogue-evoked stimulation of chromaffin cells triggers the rapid translocation of ARF6 from secretory granules to the plasma membrane and the concomitant activation of PLD in the plasma membrane (23).…”

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confidence: 99%

Identification of a Plasma Membrane-associated Guanine Nucleotide Exchange Factor for ARF6 in Chromaffin Cells

Caumont¹,

Vitale²,

Gensse³

et al. 2000

Journal of Biological Chemistry

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ADP-ribosylation factors (ARFs)1 are a group of structurally related GTP-binding proteins that form a subset of the Ras superfamily. ARFs are ubiquitous in eukaryotic cells with an amino acid sequence that is highly conserved across diverse species, suggesting a fundamental role in cellular physiology. Initially discovered as cofactors of the cholera toxin-catalyzed ADP-ribosylation of G␣ s (1), ARFs appear to be critical to vesicular trafficking in various subcellular compartments of the cell (2). More recently, members of the ARF family have been shown to activate phospholipase D (PLD) in several cellular systems as well as in isolated membranes (3-5). The ARF family has been divided into three classes based on size, sequence homology, gene structure, and phylogenetic analysis. Class I ARFs (ARFs 1-3) were initially identified as components of vesicles that originate from the Golgi (6, 7) and the endoplasmic reticulum (8), whereas class III ARF6, which is the most structurally divergent member of the family, has more recently been implicated in the exocytotic and endocytotic pathways at the plasma membrane (9 -12). Little is known about class II ARF4 and ARF5. Like other G proteins, ARFs cycle between a GDP-bound and a GTP-bound conformation. The GTP-induced conformational change is the "on" signal that permits the ARF proteins to bind to and activate specific protein effectors. Isolated ARFs have little detectable GTPase activity and exchange bound nucleotide very slowly. In cells, their GTPase cycle requires an interaction with GTPase-activating proteins and guanine-nucleotide exchange factors (GEFs) which catalyze the nucleotide exchange activity on ARF. The identification of ARF1 GEFs was facilitated by the discovery that the fungal metabolite brefeldin A (BFA) disrupts Golgi trafficking by inhibiting a Golgi-associated ARF1 exchange factor (13). Several GEF activities have been described, but the breakthrough toward the identification of GEFs acting on ARF proteins was the cloning of two related BFA-sensitive ARF1 GEFs-encoding genes in yeast Saccharomyces cerevisiae, Gea1 and Gea2 (14). This lead to the discovery of cytohesin-1 (15), ARNO (ARF nucleotidebinding-site opener, Ref. 16), and GRP1 (17) which promote guanine nucleotide exchange on ARF1 by a BFA-insensitive catalytic mechanism. Subsequent studies demonstrated that ARNO, GRP1, and cytohesin-1 can also promotes GDP/GTP exchange on ARF6 in both cell free and intact cell assays

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“…ARF6 also has been localized on endosomes (30,31) and on secretory granules (32), where it is believed to participate in endocytotic and exocytotic trafficking events. Interestingly, GIT proteins were identified in a yeast two-hybrid screen through their ability to interact with GRK2.…”

Section: Table I Zinc Content Of Arf Gaps Assessed By Inductively-coumentioning

confidence: 99%

GIT Proteins, A Novel Family of Phosphatidylinositol 3,4,5-Trisphosphate-stimulated GTPase-activating Proteins for ARF6

Vitale¹,

Patton²,

Moss³

et al. 2000

Journal of Biological Chemistry

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144

111

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ADP-ribosylation factor (ARF) proteins are key players in numerous vesicular trafficking events ranging from the formation and fusion of vesicles in the Golgi apparatus to exocytosis and endocytosis. To complete their GTPase cycle, ARFs require a guanine nucleotideexchange protein to catalyze replacement of GDP by GTP and a GTPase-activating protein (GAP) to accelerate hydrolysis of bound GTP. Recently numerous guanine nucleotide-exchange proteins and GAP proteins have been identified and partially characterized. Every ARF GAP protein identified to date contains a characteristic zinc finger motif. GIT1 and GIT2, two members of a new family of G protein-coupled receptor kinaseinteracting proteins, also contain a putative zinc finger motif and display ARF GAP activity. Truncation of the amino-terminal region containing the zinc finger motif prevented GAP activity of GIT1. One zinc molecule was found associated per molecule of purified recombinant ARF-GAP1, GIT1, and GIT2 proteins, suggesting the zinc finger motifs of ARF GAPs are functional and should play an important role in their GAP activity. Unlike ARF-GAP1, GIT1 and GIT2 stimulate hydrolysis of GTP bound to ARF6. Accordingly we found that the phospholipid dependence of the GAP activity of ARF-GAP1 and GIT proteins was quite different, as the GIT proteins are stimulated by phosphatidylinositol 3,4,5-trisphosphate whereas ARF-GAP1 is stimulated by phosphatidylinositol 4,5-bisphosphate and diacylglycerol. These results suggest that although the mechanism of GTP hydrolysis is probably very similar in these two families of ARF GAPs, GIT proteins might specifically regulate the activity of ARF6 in cells in coordination with phosphatidylinositol 3-kinase signaling pathways.

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Regulated Exocytosis in Chromaffin Cells

Cited by 124 publications

References 42 publications

The ADP ribosylation factor nucleotide exchange factor ARNO promotes β-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization

The ADP ribosylation factor nucleotide exchange factor ARNO promotes β-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization

Identification of a Plasma Membrane-associated Guanine Nucleotide Exchange Factor for ARF6 in Chromaffin Cells

GIT Proteins, A Novel Family of Phosphatidylinositol 3,4,5-Trisphosphate-stimulated GTPase-activating Proteins for ARF6

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