10 results on '"Dystrophin-Associated Proteins"'
Search Results
2. Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group
- Author
-
Irvin, Marguerite R, Sitlani, Colleen M, Floyd, James S, Psaty, Bruce M, Bis, Joshua C, Wiggins, Kerri L, Whitsel, Eric A, Sturmer, Til, Stewart, James, Raffield, Laura, Sun, Fangui, Liu, Ching-Ti, Xu, Hanfei, Cupples, Adrienne L, Tanner, Rikki M, Rossing, Peter, Smith, Albert, Zilhão, Nuno R, Launer, Lenore J, Noordam, Raymond, Rotter, Jerome I, Yao, Jie, Li, Xiaohui, Guo, Xiuqing, Limdi, Nita, Sundaresan, Aishwarya, Lange, Leslie, Correa, Adolfo, Stott, David J, Ford, Ian, Jukema, J Wouter, Gudnason, Vilmundur, Mook-Kanamori, Dennis O, Trompet, Stella, Palmas, Walter, Warren, Helen R, Hellwege, Jacklyn N, Giri, Ayush, O'donnell, Christopher, Hung, Adriana M, Edwards, Todd L, Ahluwalia, Tarunveer S, Arnett, Donna K, and Avery, Christy L
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Cardiovascular ,Human Genome ,Hypertension ,Genetics ,Black or African American ,Aged ,Antihypertensive Agents ,Blood Pressure ,Case-Control Studies ,DNA (Cytosine-5-)-Methyltransferases ,DNA Methyltransferase 3A ,DNA-Binding Proteins ,Drug Resistance ,Dystrophin-Associated Proteins ,Europe ,Female ,Genetic Loci ,Genome-Wide Association Study ,Humans ,Male ,Middle Aged ,Myosin Heavy Chains ,Myosin Type V ,Neuropeptides ,Pharmacogenetics ,Pharmacogenomic Variants ,Polymorphism ,Single Nucleotide ,Risk Assessment ,Risk Factors ,Transcription Factors ,United States ,White People ,blood pressure ,hypertension ,genome-wide association study ,severe hypertension ,treatment-resistant hypertension ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
BackgroundOnly a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.MethodsWe conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (
- Published
- 2019
3. Quantification of the transferability of a designed protein specificity switch reveals extensive epistasis in molecular recognition.
- Author
-
Melero, Cristina, Ollikainen, Noah, Harwood, Ian, Karpiak, Joel, and Kortemme, Tanja
- Subjects
computational design ,interface evolution ,promiscuity ,protein interaction domains ,recognition specificity ,Dystrophin-Associated Proteins ,Epistasis ,Genetic ,Models ,Molecular ,Mutation ,Nitric Oxide Synthase Type I ,PDZ Domains ,Protein Engineering ,Thermodynamics - Abstract
Reengineering protein-protein recognition is an important route to dissecting and controlling complex interaction networks. Experimental approaches have used the strategy of second-site suppressors, where a functional interaction is inferred between two proteins if a mutation in one protein can be compensated by a mutation in the second. Mimicking this strategy, computational design has been applied successfully to change protein recognition specificity by predicting such sets of compensatory mutations in protein-protein interfaces. To extend this approach, it would be advantageous to be able to transplant existing engineered and experimentally validated specificity changes to other homologous protein-protein complexes. Here, we test this strategy by designing a pair of mutations that modulates peptide recognition specificity in the Syntrophin PDZ domain, confirming the designed interaction biochemically and structurally, and then transplanting the mutations into the context of five related PDZ domain-peptide complexes. We find a wide range of energetic effects of identical mutations in structurally similar positions, revealing a dramatic context dependence (epistasis) of designed mutations in homologous protein-protein interactions. To better understand the structural basis of this context dependence, we apply a structure-based computational model that recapitulates these energetic effects and we use this model to make and validate forward predictions. Although the context dependence of these mutations is captured by computational predictions, our results both highlight the considerable difficulties in designing protein-protein interactions and provide challenging benchmark cases for the development of improved protein modeling and design methods that accurately account for the context.
- Published
- 2014
4. Snapin is Critical for Presynaptic Homeostatic Plasticity
- Author
-
Dickman, Dion K, Tong, Amy, and Davis, Graeme W
- Subjects
Genetics ,Schizophrenia ,Neurosciences ,Mental Health ,Brain Disorders ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Carrier Proteins ,Drosophila Proteins ,Drosophila melanogaster ,Dysbindin ,Dystrophin-Associated Proteins ,Electrophysiological Phenomena ,Homeostasis ,Immunohistochemistry ,Neuromuscular Junction ,Neuronal Plasticity ,Presynaptic Terminals ,Real-Time Polymerase Chain Reaction ,SNARE Proteins ,Signal Transduction ,Synaptic Transmission ,Synaptosomal-Associated Protein 25 ,Vesicular Transport Proteins ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
The molecular mechanisms underlying the homeostatic modulation of presynaptic neurotransmitter release are largely unknown. We have previously used an electrophysiology-based forward genetic screen to assess the function of >400 neuronally expressed genes for a role in the homeostatic control of synaptic transmission at the neuromuscular junction of Drosophila melanogaster. This screen identified a critical function for dysbindin, a gene linked to schizophrenia in humans (Dickman and Davis, 2009). Biochemical studies in other systems have shown that Snapin interacts with Dysbindin, prompting us to test whether Snapin might be involved in the mechanisms of synaptic homeostasis. Here, we demonstrate that loss of snapin blocks the homeostatic modulation of presynaptic vesicle release following inhibition of postsynaptic glutamate receptors. This is true for both the rapid induction of synaptic homeostasis induced by pharmacological inhibition of postsynaptic glutamate receptors, and the long-term expression of synaptic homeostasis induced by the genetic deletion of the muscle-specific GluRIIA glutamate receptor subunit. Loss of snapin does not alter baseline synaptic transmission, synapse morphology, synapse growth, or the number or density of active zones, indicating that the block of synaptic homeostasis is not a secondary consequence of impaired synapse development. Additional genetic evidence suggests that snapin functions in concert with dysbindin to modulate vesicle release and possibly homeostatic plasticity. Finally, we provide genetic evidence that the interaction of Snapin with SNAP25, a component of the SNARE complex, is also involved in synaptic homeostasis.
- Published
- 2012
5. Dysbindin promotes the post-endocytic sorting of G protein-coupled receptors to lysosomes.
- Author
-
Marley, Aaron and von Zastrow, Mark
- Subjects
Cell Line ,Hela Cells ,Lysosomes ,Humans ,Intercellular Signaling Peptides and Proteins ,Proteins ,Carrier Proteins ,Dystrophin-Associated Proteins ,Green Fluorescent Proteins ,Receptors ,G-Protein-Coupled ,Receptors ,Dopamine D2 ,Microscopy ,Fluorescence ,Immunoblotting ,Immunoprecipitation ,Endocytosis ,RNA Interference ,Protein Binding ,Protein Transport ,Time Factors ,Endosomal Sorting Complexes Required for Transport ,ErbB Receptors ,Dysbindin ,HeLa Cells ,Receptor ,Epidermal Growth Factor ,Receptors ,G-Protein-Coupled ,Dopamine D2 ,Microscopy ,Fluorescence ,General Science & Technology - Abstract
BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/principal findingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/significanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis.
- Published
- 2010
6. The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth
- Author
-
Ghiani, CA, Starcevic, M, Rodriguez-Fernandez, IA, Nazarian, R, Cheli, VT, Chan, LN, Malvar, JS, de Vellis, J, Sabatti, C, and Dell'Angelica, EC
- Subjects
Schizophrenia ,Mental Health ,Brain Disorders ,Genetics ,Neurosciences ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Neurological ,Analysis of Variance ,Animals ,Animals ,Newborn ,Carrier Proteins ,Cattle ,Cells ,Cultured ,Dysbindin ,Dystrophin-Associated Proteins ,Embryo ,Mammalian ,Gene Expression Regulation ,Developmental ,Hippocampus ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mutation ,Nerve Tissue Proteins ,Neurites ,Neurons ,Protein Binding ,Protein Transport ,Qa-SNARE Proteins ,Recombinant Proteins ,SNARE Proteins ,Synaptosomal-Associated Protein 25 ,Vesicle-Associated Membrane Protein 2 ,schizophrenia ,DTNBP1 ,pallidin ,synaptosomal-associated protein ,biological plausibility ,neurite extension ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis.
- Published
- 2010
7. The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.
- Author
-
Ghiani, CA, Starcevic, M, Rodriguez-Fernandez, IA, Nazarian, R, Cheli, VT, Chan, LN, Malvar, JS, de Vellis, J, Sabatti, C, and Dell'Angelica, EC
- Subjects
Hippocampus ,Neurons ,Neurites ,Cells ,Cultured ,Animals ,Mice ,Inbred C57BL ,Animals ,Newborn ,Mice ,Knockout ,Cattle ,Mice ,Carrier Proteins ,Dystrophin-Associated Proteins ,Nerve Tissue Proteins ,Recombinant Proteins ,Analysis of Variance ,Gene Expression Regulation ,Developmental ,Protein Binding ,Protein Transport ,Mutation ,SNARE Proteins ,Qa-SNARE Proteins ,Synaptosomal-Associated Protein 25 ,Vesicle-Associated Membrane Protein 2 ,Embryo ,Mammalian ,Dysbindin ,schizophrenia ,DTNBP1 ,pallidin ,synaptosomal-associated protein ,biological plausibility ,neurite extension ,Psychiatry ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences - Abstract
Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis.
- Published
- 2010
8. Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes
- Author
-
Marley, Aaron and von Zastrow, Mark
- Subjects
Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Carrier Proteins ,Cell Line ,Dysbindin ,Dystrophin-Associated Proteins ,Endocytosis ,Endosomal Sorting Complexes Required for Transport ,ErbB Receptors ,Green Fluorescent Proteins ,HeLa Cells ,Humans ,Immunoblotting ,Immunoprecipitation ,Intercellular Signaling Peptides and Proteins ,Lysosomes ,Microscopy ,Fluorescence ,Protein Binding ,Protein Transport ,Proteins ,RNA Interference ,Receptors ,Dopamine D2 ,Receptors ,G-Protein-Coupled ,Time Factors ,Hela Cells ,General Science & Technology - Abstract
BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/principal findingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/significanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis.
- Published
- 2010
9. Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice.
- Author
-
Jentsch, James David, Trantham-Davidson, Heather, Jairl, Corey, Tinsley, Matthew, Cannon, Tyrone D, and Lavin, Antonieta
- Subjects
Pyramidal Cells ,Prefrontal Cortex ,Neural Pathways ,Presynaptic Terminals ,Synapses ,Animals ,Mice ,Inbred DBA ,Mice ,Knockout ,Mice ,Memory Disorders ,Glutamic Acid ,Carrier Proteins ,Dystrophin-Associated Proteins ,Memory ,Short-Term ,Space Perception ,Neuropsychological Tests ,Synaptic Transmission ,Membrane Potentials ,Evoked Potentials ,Excitatory Postsynaptic Potentials ,Male ,Dysbindin ,working memory ,schizophrenia ,glutamate ,cognition ,excitatory ,pre-synaptic ,Inbred DBA ,Knockout ,Memory ,Short-Term ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, in which it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological, and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants showed impairments of spatial working memory compared with wild-type controls; heterozygous mice showed intermediate levels of cognitive dysfunction. Deep-layer pyramidal neurons recorded in the prefrontal cortex of mutant mice showed reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in the prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending on this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.
- Published
- 2009
10. Dysbindin Modulates Prefrontal Cortical Glutamatergic Circuits and Working Memory Function in Mice
- Author
-
Jentsch, James David, Trantham-Davidson, Heather, Jairl, Corey, Tinsley, Matthew, Cannon, Tyrone D, and Lavin, Antonieta
- Subjects
Neurosciences ,Basic Behavioral and Social Science ,Genetics ,Schizophrenia ,Brain Disorders ,Mental Health ,Behavioral and Social Science ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,1.1 Normal biological development and functioning ,Mental health ,Neurological ,Animals ,Carrier Proteins ,Dysbindin ,Dystrophin-Associated Proteins ,Evoked Potentials ,Excitatory Postsynaptic Potentials ,Glutamic Acid ,Male ,Membrane Potentials ,Memory Disorders ,Memory ,Short-Term ,Mice ,Mice ,Inbred DBA ,Mice ,Knockout ,Neural Pathways ,Neuropsychological Tests ,Prefrontal Cortex ,Presynaptic Terminals ,Pyramidal Cells ,Space Perception ,Synapses ,Synaptic Transmission ,working memory ,schizophrenia ,glutamate ,cognition ,excitatory ,pre-synaptic ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, in which it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological, and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants showed impairments of spatial working memory compared with wild-type controls; heterozygous mice showed intermediate levels of cognitive dysfunction. Deep-layer pyramidal neurons recorded in the prefrontal cortex of mutant mice showed reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in the prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending on this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.
- Published
- 2009
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.