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At least 919 records · Page 51Linked to original sources
PubMed2006

Internalization of large double-membrane intercellular vesicles by a clathrin-dependent endocytic process.

Beyond its well-documented role in vesicle endocytosis, clathrin has also been implicated in the internalization of large particles such as viruses, pathogenic bacteria, and even latex beads. We have discovered an additional clathrin-dependent endocytic process that results in the internalization of large, double-membrane vesicles at lateral membranes of cells that are coupled by gap junctions (GJs). GJ channels bridge apposing cell membranes to mediate the direct transfer of electrical currents and signaling molecules from cell to cell. Here, we report that entire GJ plaques, clusters of GJ channels, can be internalized to form large, double-membrane vesicles previously termed annular gap junctions (AGJs). These internalized AGJ vesicles subdivide into smaller vesicles that are degraded by endo/lysosomal pathways. Mechanistic analyses revealed that clathrin-dependent endocytosis machinery-components, including clathrin itself, the alternative clathrin-adaptor Dab2, dynamin, myosin-VI, and actin are involved in the internalization, inward movement, and degradation of these large, intercellular double-membrane vesicles. These findings contribute to the understanding of clathrin's numerous emerging functions.

Actin Cytoskeleton↗
PubMed1993

A genetic analysis of the stoned locus and its interaction with dunce, shibire and Suppressor of stoned variants of Drosophila melanogaster.

The genetic complementation patterns of both behavioral and lethal alleles at the stoned locus have been characterized. Mosaic analysis of a stoned lethal allele suggests that stoned functions either in the nervous system or in both the nervous system and musculature, but is not required for gross neural development. The behavioral alleles stnts and stnC, appear to be defective in a diametrically opposite sense, show interallelic complementation, and indicate distinct roles for the stoned gene product in the visual system and in motor coordination. A number of other neurological mutations have been investigated for their possible interaction with the viable stoned alleles. Mutations at two loci, dunce and shibire, act synergistically with the stnts mutations to cause lethality, but fail to interact with stnC. A third variant (Suppressor of stoned) has been identified which can suppress the debilitation associated with the stnts mutations. These data, together with a previously identified interaction between the stnts and tan mutants, indicate a central role for the stoned gene product in neuronal function, and suggests that the stoned gene product interacts, either directly or indirectly, with the neural cAMP second messenger system, with the synaptic membrane recycling pathway via dynamin, and with biogenic amine metabolism.

Alleles↗
PubMed2004

Bordetella dermonecrotic toxin exerting toxicity through activation of the small GTPase Rho.

Bordetella dermonecrotic toxin (DNT) is a virulence factor produced by bacteria belonging to the genus Bordetella. The toxin possesses novel transglutaminase activity that catalyzes polyamination or deamidation of the small GTPases of the Rho family. The modified GTPases loose their GTP hydrolyzing activity, function as a constitutive active molecule, and continuously transduce signals to downstream effectors, which mediate the consequent phenotypes of cells intoxicated by DNT. A dynamin-dependent endocytosis is required for the toxin to be internalized into cells although it is unlikely transported to deep organelles such as the Golgi apparatus or the ER. Several lines of evidence show that the toxin undergoes proteolytic cleavage by furin or furin-like protease probably in the early endosome, and then escapes into the cytoplasm to reach the GTPase.

ADP Ribose Transferases↗
PubMed2003

Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/dynamin during tracheal development.

Human nm23 has been implicated in suppression of metastasis in various cancers, but the underlying mechanism of such activity has not been fully understood. Using Drosophila tracheal system as a genetic model, we examined the function of the Drosophila homolog of nm23, the awd gene, in cell migration. We show that loss of Drosophila awd results in dysregulated tracheal cell motility. This phenotype can be suppressed by reducing the dosage of the chemotactic FGF receptor (FGFR) homolog, breathless (btl), indicating that btl and awd are functionally antagonists. In addition, mutants of shi/dynamin show similar tracheal phenotypes as in awd and exacerbate those in awd mutant, suggesting defects in vesicle-mediated turnover of FGFR in the awd mutant. Consistent with this, Btl-GFP chimera expressed from a cognate btl promoter-driven system accumulate at high levels on tracheal cell membrane of awd mutants as well as in awd RNA duplex-treated cultured cells. Thus, we propose that awd regulates tracheal cell motility by modulating the FGFR levels, through a dynamin-mediated pathway.

Animals↗
PubMed2005

DRP1A is responsible for vascular continuity synergistically working with VAN3 in Arabidopsis.

In most dicotyledonous plants, vascular tissues in the leaf have a reticulate venation pattern. We have isolated and characterized an Arabidopsis (Arabidopsis thaliana) mutant defective in the vascular network defective mutant, van3. van3 mutants show a discontinuous vascular pattern, and VAN3 is known to encode an ADP-ribosylation-factor-GTPase-activating protein that regulates membrane trafficking in the trans-Golgi network. To elucidate the molecular nature controlling the vein patterning process through membrane trafficking, we searched VAN3-interacting proteins using a yeast (Saccharomyces cerevisiae) two hybrid system. As a result, we isolated the plant Dynamin-Related Protein 1A (DRP1A) as a VAN3 interacting protein. The spatial and temporal expression patterns of DRP1AGUS and VAN3GUS were very similar. The subcellular localization of VAN3 completely overlapped to that of DRP1A. drp1a showed a disconnected vascular network, and the drp1a mutation enhanced the phenotype of vascular discontinuity of the van3 mutant in the drp1a van3 double mutant. Furthermore, the drp1 mutation enhanced the discontinuous vascular pattern of the gnom mutant, which had the same effect as that of the van3 mutation. These results indicate that DRP1 modulates the VAN3 function in vesicle budding from the trans-Golgi network, which regulates vascular formation in Arabidopsis.

ADP-Ribosylation Factors↗
PubMed2001

Three-dimensional analysis of syncytial-type cell plates during endosperm cellularization visualized by high resolution electron tomography.

The three-dimensional architecture of syncytial-type cell plates in the endosperm of Arabidopsis has been analyzed at approximately 6-nm resolution by means of dual-axis high-voltage electron tomography of high-pressure frozen/freeze-substituted samples. Mini-phragmoplasts consisting of microtubule clusters assemble between sister and nonsister nuclei. Most Golgi-derived vesicles appear connected to these microtubules by two molecules that resemble kinesin-like motor proteins. These vesicles fuse with each other to form hourglass-shaped intermediates, which become wide (approximately 45 nm in diameter) tubules, the building blocks of wide tubular networks. New mini-phragmoplasts also are generated de novo around the margins of expanding wide tubular networks, giving rise to new foci of cell plate growth, which later become integrated into the main cell plate. Spiral-shaped rings of the dynamin-like protein ADL1A constrict but do not fission the wide tubules at irregular intervals. These rings appear to maintain the tubular geometry of the network. The wide tubular network matures into a convoluted fenestrated sheet in a process that involves increases of 45 and 130% in relative membrane surface area and volume, respectively. The proportionally larger increase in volume appears to reflect callose synthesis. Upon fusion with the parental plasma membrane, the convoluted fenestrated sheet is transformed into a planar fenestrated sheet. This transformation involves clathrin-coated vesicles that reduce the relative membrane surface area and volume by approximately 70%. A ribosome-excluding matrix encompasses the cell plate membranes from the fusion of the first vesicles until the onset of the planar fenestrated sheet formation. We postulate that this matrix contains the molecules that mediate cell plate assembly.

Arabidopsis↗
PubMed2005

The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function.

The osteoclast resorbs mineralized bone during bone development, homeostasis, and repair. The deletion of the gene encoding the nonreceptor tyrosine kinase c-Src produces an osteopetrotic skeletal phenotype that is the consequence of the inability of the mature osteoclast to efficiently resorb bone. Src-/- osteoclasts exhibit reduced motility and abnormal organization of the apical secretory domain (the ruffled border) and attachment-related cytoskeletal elements that are necessary for bone resorption. A key function of Src in osteoclasts is to promote the rapid assembly and disassembly of the podosomes, the specialized integrin-based attachment structures of osteoclasts and other highly motile cells. Once recruited to the activated integrins, especially alphavbeta3), by the adhesion tyrosine kinase Pyk2, Src binds and phosphorylates Cbl and Cbl-b, homologous multisite adapter proteins with ubiquitin ligase activity. The Cbl proteins in turn recruit and activate additional signaling effectors, including phosphatidylinositol 3-kinase and dynamin, which play key roles in the development of cell polarity and the regulation of cell attachment and motility. In addition, Src and the Cbl proteins contribute to signaling cascades that are activated by several important receptors, including receptor activator of nuclear factor kappaB and the macrophage colony-stimulating factor receptor, and also downregulate the signaling from many of these receptors.

Animals↗
PubMed2006

Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder.

OBJECTIVE: In order to identify whether the mechanisms associated with neurotransmitter release are involved in the pathologies of bipolar disorder and schizophrenia, levels of presynaptic [synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin, vesicle-associated membrane protein, dynamin I] and structural (neuronal cell adhesion molecule and alpha-synuclein) neuronal markers were measured in Brodmann's area 9 obtained postmortem from eight subjects with bipolar I disorder (BPDI), 20 with schizophrenia and 20 controls. METHODS: Determinations of protein levels were carried out using Western blot techniques with specific antibodies. Levels of mRNA were measured using real-time polymerase chain reaction. RESULTS: In BPDI, levels of SNAP-25 (p < 0.01) and synaptophysin (p < 0.05) increased. There were no changes in schizophrenia or any other changes in BPDI. Levels of mRNA for SNAP-25 were decreased in BPDI (p < 0.05). CONCLUSION: Changes in SNAP-25 and synaptophysin in BPDI suggest that changes in specific neuronal functions could be linked to the pathology of the disorder.

Antibodies↗
PubMed2005

The Listeria protein internalin B mimics hepatocyte growth factor-induced receptor trafficking.

Increased hepatocyte growth factor receptor (HGFR) signaling correlates closely with neoplastic invasion and metastatic potential of many human cancers. Hepatocyte growth factor receptor signaling is initiated by binding the physiological ligand HGF or the internalin B (InlB) protein of Listeria monocytogenes. Subsequent degradation of endocytosed HGFR terminates receptor signaling. Previously reported discrepancies in InlB and HGF-induced HGFR signaling could reflect differences in receptor internalization and degradation in response to these distinct ligands. We report that soluble InlB and HGF are mechanistically equivalent in triggering clathrin-dependent endocytosis and lysosomal degradation of HGFR. After internalization, InlB and HGF colocalize with Rab5, EEA1 and the transferrin receptor in classical early endosomes. Hepatocyte growth factor receptor internalization was prevented by overexpression of dominant negative mutants of dynamin 1 and epidermal growth factor phosphorylation substrate 15, but not caveolin 1, the GTPase Arf6 or the cholesterol-chelating drug Nystatin. Thus, HGFR internalization is principally clathrin-mediated and is not regulated by clathrin- independent pathways. Phosphatidylinositol 3-kinase signaling and HGF-regulated tyrosine kinase substrate were not required for ligand-triggered internalization of HGFR but were essential for subsequent lysosomal degradation. Thus, soluble InlB and HGF induce HGFR endocytosis and degradation by indistinguishable mechanisms, suggesting that InlB may be exploited to regulate pathogenic HGFR signaling.

ADP-Ribosylation Factor 6↗
PubMed2006

Thyrotropin-releasing hormone increases GABA release in rat hippocampus.

Thyrotropin-releasing hormone (TRH) is a tripeptide that is widely distributed in the brain including the hippocampus where TRH receptors are also expressed. TRH has anti-epileptic effects and regulates arousal, sleep, cognition, locomotion and mood. However, the cellular mechanisms underlying such effects remain to be determined. We examined the effects of TRH on GABAergic transmission in the hippocampus and found that TRH increased the frequency of GABAA receptor-mediated spontaneous IPSCs in each region of the hippocampus but had no effects on miniature IPSCs or evoked IPSCs. TRH increased the action potential firing frequency recorded from GABAergic interneurons in CA1 stratum radiatum and induced membrane depolarization suggesting that TRH increases the excitability of interneurons to facilitate GABA release. TRH-induced inward current had a reversal potential close to the K+ reversal potential suggesting that TRH inhibits resting K+ channels. The involved K+ channels were sensitive to Ba2+ but resistant to other classical K+ channel blockers, suggesting that TRH inhibits the two-pore domain K+ channels. Because the effects of TRH were mediated via Galphaq/11, but were independent of its known downstream effectors, a direct coupling may exist between Galphaq/11 and K+ channels. Inhibition of the function of dynamin slowed the desensitization of TRH responses. TRH inhibited seizure activity induced by Mg2+ deprivation, but not that generated by picrotoxin, suggesting that TRH-mediated increase in GABA release contributes to its anti-epileptic effects. Our results demonstrate a novel mechanism to explain some of the hippocampal actions of TRH.

Action Potentials↗
PubMed2000

The platelet-derived growth factor receptor stimulation of p42/p44 mitogen-activated protein kinase in airway smooth muscle involves a G-protein-mediated tyrosine phosphorylation of Gab1.

Using cultured airway smooth muscle cells, we showed previously that the platelet-derived growth factor (PDGF) receptor uses the G-protein, G(i), to stimulate Grb-2-associated phosphoinositide 3-kinase (PI3K) activity. We also showed that this was an intermediate step in the activation of p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) by PDGF. We now present two lines of evidence that provide further support for this model. First, we report that PDGF stimulates the G(i)-mediated tyrosine phosphorylation of the Grb-2 adaptor protein, Gab1. This phosphorylation appears to be necessary for association of PI3K1a with the Gab1-Grb-2 complex. Second, PI3K appears to promote the subsequent association of dynamin II (which is involved in clathrin-mediated endocytic processing) with the complex. Furthermore, inhibitors of PI3K and clathrin-mediated endocytosis reduced the PDGF-dependent activation of p42/p44 MAPK, suggesting a role for PI3K in the endocytic signaling process leading to stimulation of p42/p44 MAPK. Together, these results begin to define a common signaling model for certain growth factor receptors (e.g., PDGF, insulin, insulin-like growth factor-1, and fibroblast growth factor) which use G(i) to transmit signals to p42/p44 MAPK.

Animals↗
PubMed2001

Cell-type specific effects of endocytosis inhibitors on 5-hydroxytryptamine(2A) receptor desensitization and resensitization reveal an arrestin-, GRK2-, and GRK5-independent mode of regulation in human embryonic kidney 293 cells.

The effect of endocytosis inhibitors on 5-hydroxytryptamine(2A) (5-HT(2A)) receptor desensitization and resensitization was examined in transiently transfected human embryonic kidney (HEK) 293 cells and in C6 glioma cells that endogenously express 5-HT(2A) receptors. In HEK-293 cells, 5-HT(2A) receptor desensitization was unaffected by cotransfection with a dominant-negative mutant of dynamin (DynK44A), a truncation mutant of arrestin-2 [Arr2(319-418)], or by two well-characterized chemical inhibitors of endocytosis: concanavalin A (conA) and phenylarsine oxide (PAO). In contrast, beta 2-adrenergic receptor desensitization was significantly potentiated by each of these treatments in HEK-293 cells. In C6 glioma cells, however, DynK44A, Arr2(319-418), conA, and PAO each resulted in the potentiation of 5-HT(2A) and beta-adrenergic receptor desensitization. The cell-type-specific effect of Arr2(319-418) on 5-HT(2A) receptor desensitization was not related to the level of GRK2 or GRK5 expression. Interestingly, although beta 2-adrenergic receptor resensitization was potently blocked by cotransfection with DynK44A, 5-HT(2A) receptor resensitization was enhanced, suggesting the existence of a novel cell-surface mechanism for 5-HT(2A) receptor resensitization in HEK-293 cells. In addition, Arr2(319-418) had no effect on 5-HT(2A) receptor resensitization in HEK-293 cells, although it attenuated the resensitization of the beta 2-adrenergic receptor. However, in C6 glioma cells, both DynK44A and Arr2(319-418) significantly reduced 5-HT(2A) receptor resensitization. Taken together, these results provide the first convincing evidence of cell-type-specific roles for endocytosis inhibitors in regulating GPCR activity. Additionally, these results imply that novel GRK and arrestin-independent mechanisms of 5-HT(2A) receptor desensitization and resensitization exist in HEK-293 cells.

Animals↗
PubMed2003

Spatial regulation of Galphai protein signaling in clathrin-coated membrane microdomains containing GAIP.

Regulators of G-protein signaling (RGS) proteins are GTPase-activating proteins (GAPs) that bind to Galpha subunits and attenuate G protein signaling, but where these events occur in the cell is not yet established. Here we investigated, by immunofluorescence labeling and deconvolution analysis, the site at which endogenous Galpha-interacting protein (GAIP) (RGS19) binds to Galphai3-YFP and its fate after activation of delta-opioid receptor (DOR). In the absence of agonist, GAIP is spatially segregated from Galphai3 and DOR in clathrin-coated domains (CCPs) of the cell membrane (PM), whereas Galphai3-YPF and DOR are located in non-clathrin-coated microdomains of the PM. Upon addition of agonist, Galphai3 partially colocalizes with GAIP in CCPs at the PM. When endocytosis is blocked by expression of a dynamin mutant [dyn(K44A)], there is a striking overlap in the distribution of DOR and Galphai3-YFP with GAIP in CCPs. Moreover, Galphai3-YFP and GAIP form a coprecipitable complex. Our results support a model whereby, after agonist addition, DOR and Galphai3 move together into CCPs where Galphai3 and GAIP meet and turn off G protein signaling. Subsequently, Galphai3 returns to non-clathrin-coated microdomains of the PM, GAIP remains stably associated with CCPs, and DOR is internalized via clathrin-coated vesicles. This constitutes a novel mechanism for regulation of Galpha signaling through spatial segregation of a GAP in clathrin-coated pits.

Adaptor Protein Complex 2↗
PubMed2004

Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2).

We examined the role of G-protein coupled receptor kinase-2 (GRK2) in the homologous desensitization of mGlu4 metabotropic glutamate receptors transiently expressed in human embryonic kidney (HEK) 293 cells. Receptor activation with the agonist l-2-amino-4-phosphonobutanoate (l-AP4) stimulated at least two distinct signaling pathways: inhibition of cAMP formation and activation of the mitogen-activated protein kinase (MAPK) pathway [assessed by Western blot analysis of phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2]. Activation of both pathways was attenuated by pertussis toxin. Overexpression of GRK2 (but not GRK4) largely attenuated the stimulation of the MAPK pathway by l-AP4, whereas it slightly potentiated the inhibition of FSK-stimulated cAMP formation. Transfection with a kinase-dead mutant of GRK2 (GRK2-K220R) or with the C-terminal fragment of GRK2 also reduced the mGlu4-mediated stimulation of MAPK, suggesting that GRK2 binds to the Gbetagamma subunits to inhibit signal propagation toward the MAPK pathway. This was confirmed by the evidence that GRK2 coimmunoprecipitated with Gbetagamma subunits in an agonist-dependent manner. Finally, neither GRK2 nor its kinase-dead mutant had any effect on agonist-induced mGlu4 receptor internalization in HEK293 cells transiently transfected with GFP-tagged receptors. Agonist-dependent internalization was instead abolished by a negative-dominant mutant of dynamin, which also reduced the stimulation of MAPK pathway by l-AP4. We speculate that GRK2 acts as a "switch molecule" by inhibiting the mGlu4 receptor-mediated stimulation of MAPK and therefore directing the signal propagation toward the inhibition of adenylyl cyclase.

Cell Line↗
PubMed2001

The role of Drosophila mushroom body signaling in olfactory memory.

The mushroom bodies of the Drosophila brain are important for olfactory learning and memory. To investigate the requirement for mushroom body signaling during the different phases of memory processing, we transiently inactivated neurotransmission through this region of the brain by expressing a temperature-sensitive allele of the shibire dynamin guanosine triphosphatase, which is required for synaptic transmission. Inactivation of mushroom body signaling through alpha/beta neurons during different phases of memory processing revealed a requirement for mushroom body signaling during memory retrieval, but not during acquisition or consolidation.

Afferent Pathways↗
PubMed2003

Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration.

Mutations in proteins of the Drosophila phototransduction cascade, a prototypic guanine nucleotide-binding protein-coupled receptor signaling system, lead to retinal degeneration and have been used as models to understand human degenerative disorders. Here, modulating the sphingolipid biosynthetic pathway rescued retinal degeneration in Drosophila mutants. Targeted expression of Drosophila neutral ceramidase rescued retinal degeneration in arrestin and phospholipase C mutants. Decreasing flux through the de novo sphingolipid biosynthetic pathway also suppressed degeneration in these mutants. Both genetic backgrounds modulated the endocytic machinery because they suppressed defects in a dynamin mutant. Suppression of degeneration in arrestin mutant flies expressing ceramidase correlated with a decrease in ceramide levels. Thus, enzymes of sphingolipid metabolism may be suitable targets in the therapeutic management of retinal degeneration.

Acyltransferases↗
PubMed2003

The division of endosymbiotic organelles.

Mitochondria and chloroplasts are essential eukaryotic organelles of endosymbiotic origin. Dynamic cellular machineries divide these organelles. The mechanisms by which mitochondria and chloroplasts divide were thought to be fundamentally different because chloroplasts use proteins derived from the ancestral prokaryotic cell division machinery, whereas mitochondria have largely evolved a division apparatus that lacks bacterial cell division components. Recent findings indicate, however, that both types of organelles universally require dynamin-related guanosine triphosphatases to divide. This mechanistic link provides fundamental insights into the molecular events driving the division, and possibly the evolution, of organelles in eukaryotes.

Animals↗
PubMed2005

Nucleus accumbens long-term depression and the expression of behavioral sensitization.

Drug-dependent neural plasticity related to drug addiction and schizophrenia can be modeled in animals as behavioral sensitization, which is induced by repeated noncontingent or self-administration of many drugs of abuse. Molecular mechanisms that are critical for behavioral sensitization have yet to be specified. Long-term depression (LTD) of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR)-mediated synaptic transmission in the brain has been proposed as a cellular substrate for learning and memory. The expression of LTD in the nucleus accumbens (NAc) required clathrin-dependent endocytosis of postsynaptic AMPARs. NAc LTD was blocked by a dynamin-derived peptide that inhibited clathrin-mediated endocytosis or by a GluR2-derived peptide that blocked regulated AMPAR endocytosis. Systemic or intra-NAc infusion of the membrane-permeable GluR2 peptide prevented the expression of amphetamine-induced behavioral sensitization in the rat.

Animals↗