Disease relevance of Dnm1

• We focused on the coupling of these processes by observing the secretory vesicle marker synaptobrevin and the endocytotic vesicle marker dynamin I tagged with green and red fluorescent proteins under an evanescent wave microscope in pheochromocytoma cells [1].
• To further elucidate functions of dynamin II, the pleckstrin homology domain (PHD), the proline-rich domain (PRD), and the C-terminal part of dynamin II (dynamin(500-870)) were expressed in Escherichia coli [2].
• Calcium- and dynamin-independent endocytosis in dorsal root ganglion neurons [3].
• To understand the role of rat brain dynamin 1 in neuronal morphogenesis, we correlated the intracellular levels of dynamin with the formation of neurites in rat hippocampal neurons and neuroblastoma N1E-115 cells in vitro [4].
• No significant titer difference was observed when MoMuLV vector was tranduced into HeLa cells overexpressing either wild-type or mutant dynamin, while the transduction ability of vesicular stomatitis virus glycoprotein pseudotyped vector into HeLa cells overexpressing mutant dynamin was decreased significantly [5].

Psychiatry related information on Dnm1

• Modulation of Fas receptor proteins and dynamin during opiate addiction and induction of opiate withdrawal in rat brain [6].
• Fission also occurred when dynamin and GTP were added to lipid tubules that had been generated from liposomes by the motor activity of kinesin on microtubules [7].

High impact information on Dnm1

• Clathrin-coated buds and dynamin-coated tubules morphologically similar to corresponding structures observed in synaptic membranes can be generated on protein-free liposomes by incubation with cytosol, or with clathrin coat proteins and purified dynamin, respectively [8].
• Dynamin GTPase activity is stimulated by several of the bound SH3 domains, suggesting that the function of the SH3 module is not restricted to protein-protein interactions but may also include the interactive regulation of GTP-binding proteins [9].
• Synaptojanin is a nerve terminal protein of relative molecular mass 145,000 which appears to participate with dynamin in synaptic vesicle recycling [10].
• Dynamin is a GTPase implicated in synaptic vesicle endocytosis and here we show that the walls of these membranous tubules, but not their distal ends, were positive for dynamin immunoreactivity [11].
• These findings demonstrate that dynamin and clathrin act at different sites in the formation of endocytic vesicles [11].

Chemical compound and disease context of Dnm1

• Mu-opioid agonist inhibition of kappa-opioid receptor-stimulated extracellular signal-regulated kinase phosphorylation is dynamin-dependent in C6 glioma cells [12].
• Each rat in the three L-carnitine-treated groups was injected subcutaneously with L-carnitine, 50 (D50), 100 (D100), or 200 (D200) mg/kg body weight every other day for four weeks, and animals in normal (N) and diabetic (DM) groups received saline by the same method [13].

Biological context of Dnm1

• Dynamin is a 100-kDa microtubule-activated GTPase originally isolated from mammalian brain that has been proposed to be crucial in the early steps of endocytosis [14].
• Endophilin-SH3 binding to the high affinity site was disrupted when dynamin-1 PRD was phosphorylated with Cdk5, indicating that this site overlaps the phosphorylation sites, but amphiphysin-SH3 binding was unaffected [15].
• Other SH3 domains showed similarly complex binding characteristics, and substantial differences were noted between the PRDs from dynamin-1 and -2 [15].
• Preloading of dynamin-1 PRD with the amphiphysin-SH3 domain partially occluded binding of the endophilin-SH3 domain, indicating overlap between the binding sites in the C terminus, but endophilin was still able to interact with the high affinity N-terminal site [15].
• To assess the specificity and kinetics of this process, we undertook surface plasmon resonance studies of the interaction between isolated PRDs of dynamin-1 and -2 and several purified SH3 domains [15].

Anatomical context of Dnm1

• Amphiphysin (Amph) is a src homology 3 domain-containing protein that has been implicated in synaptic vesicle endocytosis as a result of its interaction with dynamin [16].
• In wild-type cells, dystroglycan formed a complex with dynamin and codistributed with cortactin at membrane ruffles, which are organelles implicated in endocytosis [17].
• Dystroglycan was associated and colocalized immunohistochemically with dynamin 1 in the central nervous system in the outer plexiform layer of retina where photoreceptor terminals are found [17].
• These data suggest that Dyn3 is a postsynaptic dynamin and, like its binding partner Homer, plays a significant role in dendritic spine morphogenesis and remodeling [18].
• In addition, dynamin-1 and amphiphysin-2 partially colocalized at the plasma membrane [19].

Associations of Dnm1 with chemical compounds

• Glutathione S-transferase-linked SH3 domains bound with high affinity (K(D) approximately 10 nm to 1 microm) to both dynamin-1 and -2 [15].
• These include the clathrin-coated buds and dynamin-coated tubules, which accumulate in nerve terminal membranes incubated in the presence of guanosine 5'-3-O-(thio)triphosphate [20].
• Thus, c-Src-mediated tyrosine phosphorylation is required for the function of dynamin in ligand-induced signaling receptor internalization [21].
• Because fission of clathrin-coated pits requires dynamin, we examined the mechanisms by which dopamine receptor signals promote dynamin-2 recruitment and assembly at the site of Na(+),K(+)-ATPase endocytosis [22].
• Dephosphorylation of amphiphysin I, like dephosphorylation of dynamin I and synaptojanin I, is inhibited by cyclosporin A and FK-506 (0.5 microM), two drugs that specifically block the Ca2+/calmodulin-dependent phosphatase 2B calcineurin, but not by okadaic acid (1 microM), which blocks protein phosphatases 1 and 2B [20].

Physical interactions of Dnm1

• Thus syndapin I is a central component of the endocytic protein complex for SVE via stimulus-dependent recruitment to dynamin I and has a key role in synaptic transmission [23].
• Amphiphysin I is an abundant presynaptic protein that interacts via its COOH-terminal src homology 3 (SH3) domain with the GTPase dynamin I and the inositol-5-phosphatase synaptojanin [20].
• This patch accounts for the specific requirement of amphiphysin for two arginines in the proline-rich binding motif to which it binds on dynamin [24].
• Mixed-lineage kinase 2-SH3 domain binds dynamin and greatly enhances activation of GTPase by phospholipid [25].

Enzymatic interactions of Dnm1

• However, dynamin was not tyrosine phosphorylated by AngII treatment and seemed to be distinct from the 100 kD phosphotyrosine protein that was found in Nck immunoprecipitates [26].

Co-localisations of Dnm1

• In unstimulated cells, the NK1R colocalized with dynamin at the plasma membrane, and Rab5a was detected in endosomes [27].

Regulatory relationships of Dnm1

• Syndapin I is the phosphorylation-regulated dynamin I partner in synaptic vesicle endocytosis [23].
• Phospholipase C-gamma1 is a guanine nucleotide exchange factor for dynamin-1 and enhances dynamin-1-dependent epidermal growth factor receptor endocytosis [28].
• Amphiphysin-dependent clathrin-coat recruitment is enhanced by the interaction of amphiphysin with dynamin [29].
• Our findings also indicate that dynamin GTPases are differentially regulated by c-Src-mediated tyrosine phosphorylation [30].
• The sigma ligand 1,3-di-O-tolylguanidine (DTG) increased basal dynamin and decreased depolarization-stimulated phosphorylation of the synaptosomal protein synapsin Ib without having direct effects on protein kinases or protein phosphatases [31].

Other interactions of Dnm1

• Amphiphysin-1 and -2 were also detected in enterochromaffin-like cells by immunohistochemistry in the same locations as dynamin-1 and -2 [19].
• Dynamin-1 and -2 were expressed at similar high levels, whereas dynamin-3 was of low abundance [19].
• Endophilin 1 is proposed to participate in synaptic vesicle biogenesis through SH3 domain-mediated interactions with the polyphosphoinositide phosphatase synaptojanin and the GTPase dynamin [32].
• Dynamin 2, a dynamin isoform, is expressed most intensely in testicular tissue; however, precise localization has never been studied [33].
• After depolarization, syndapin showed a calcineurin-mediated interaction with dynamin [23].

Analytical, diagnostic and therapeutic context of Dnm1

• Using RT-PCR and western blotting, we detected dynamin-1, -2 and -3 in highly enriched isolated enterochromaffin-like cells [19].
• Immunofluorescence microscopy located dynamin-1 and -2 to the cytoplasm and cell surface, whereas dynamin-3 was distributed differently in the perinuclear area [19].
• Molecular cloning of the microtubule-associated mechanochemical enzyme dynamin reveals homology with a new family of GTP-binding proteins [34].
• Electron microscopy reveals that, in the GTP-bound state, dynamin rings appear to be tightly packed together [35].
• In situ hybridization revealed high levels of dynamin transcripts in neural cells in the cerebellar cortex, hippocampus (particularly in the CA3 area), and cerebral cortex [36].

References