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Advocating for mutually beneficial access to shelved compounds.
Pulley JM, Jerome RN, Shirey-Rice JK, Zaleski NM, Naylor HM, Pruijssers AJ, Jackson JC, Bernard GR, Holroyd KJ
(2018) Future Med Chem 10: 1395-1398
MeSH Terms: Antidiuretic Hormone Receptor Antagonists, Anxiety Disorders, Depressive Disorder, Major, Drug Industry, Drug Repositioning, Humans, Indoles, Pyrrolidines, Receptors, Vasopressin
Added March 26, 2019
0 Communities
2 Members
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MeSH Terms
Influence of Pathogenic Mutations on the Energetics of Translocon-Mediated Bilayer Integration of Transmembrane Helices.
Schlebach JP, Sanders CR
(2015) J Membr Biol 248: 371-81
MeSH Terms: Amino Acid Sequence, Animals, Cattle, Conserved Sequence, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, KCNQ1 Potassium Channel, Lipid Bilayers, Mutation, Mutation, Missense, Myelin Proteins, Protein Structure, Secondary, Protein Transport, Receptors, Vasopressin, Rhodopsin, Thermodynamics
Show Abstract · Added November 21, 2018
Aberrant protein folding and assembly contribute to a number of diseases, and efforts to rationalize how pathogenic mutations cause this phenomenon represent an important imperative in biochemical research. However, for α-helical membrane proteins, this task is complicated by the fact that membrane proteins require intricate machinery to achieve structural and functional maturity under cellular conditions. In this work, we utilized the ΔG predictor algorithm ( www.dgpred.cbr.su.se ) to survey 470 known pathogenic mutations occurring in five misfolding-prone α-helical membrane proteins for their predicted effects on the translocon-mediated membrane integration of transmembrane helices, a critical step in biosynthesis and folding of nascent membrane proteins. The results suggest that about 10 % of these mutations are likely to have adverse effects on the topogenesis of nascent membrane proteins. These results suggest that the misfolding of a modest but nonetheless significant subset of pathogenic variants may begin at the translocon. Potential implications for therapeutic design and personalized medicine are discussed.
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MeSH Terms
A novel experimental strategy to assess the metabolic effects of selective activation of a G(q)-coupled receptor in hepatocytes in vivo.
Li JH, Jain S, McMillin SM, Cui Y, Gautam D, Sakamoto W, Lu H, Jou W, McGuinness OP, Gavrilova O, Wess J
(2013) Endocrinology 154: 3539-51
MeSH Terms: Animals, Antidiuretic Hormone Receptor Antagonists, Cells, Cultured, Diabetes Mellitus, Type 2, Enzyme Activators, Female, G-Protein-Coupled Receptor Kinases, GTP-Binding Protein alpha Subunits, Gq-G11, Gluconeogenesis, Glycogenolysis, Hepatocytes, Humans, Hypoglycemic Agents, Male, Mice, Mice, Obese, Mice, Transgenic, Protein Engineering, Protein Interaction Domains and Motifs, Receptor, Muscarinic M3, Receptors, Vasopressin, Recombinant Fusion Proteins, Specific Pathogen-Free Organisms
Show Abstract · Added July 21, 2014
Increased hepatic glucose production is a key pathophysiological feature of type 2 diabetes. Like all other cell types, hepatocytes express many G protein-coupled receptors (GPCRs) that are linked to different functional classes of heterotrimeric G proteins. The important physiological functions mediated by G(s)-coupled hepatic glucagon receptors are well-documented. In contrast, little is known about the in vivo physiological roles of hepatocyte GPCRs that are linked to G proteins of the G(q) family. To address this issue, we established a transgenic mouse line (Hep-Rq mice) that expressed a G(q)-linked designer receptor (Rq) in a hepatocyte-selective fashion. Importantly, Rq could no longer bind endogenous ligands but could be selectively activated by a synthetic drug, clozapine-N-oxide. Clozapine-N-oxide treatment of Hep-Rq mice enabled us to determine the metabolic consequences caused by selective activation of a G(q)-coupled GPCR in hepatocytes in vivo. We found that acute Rq activation in vivo led to pronounced increases in blood glucose levels, resulting from increased rates of glycogen breakdown and gluconeogenesis. We also demonstrated that the expression of the V(1b) vasopressin receptor, a G(q)-coupled receptor expressed by hepatocytes, was drastically increased in livers of ob/ob mice, a mouse model of diabetes. Strikingly, treatment of ob/ob mice with a selective V(1b) receptor antagonist led to reduced glucose excursions in a pyruvate challenge test. Taken together, these findings underscore the importance of G(q)-coupled receptors in regulating hepatic glucose fluxes and suggest novel receptor targets for the treatment of type 2 diabetes.
1 Communities
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23 MeSH Terms
Soluble mimics of the cytoplasmic face of the human V1-vascular vasopressin receptor bind arrestin2 and calmodulin.
Wu N, Macion-Dazard R, Nithianantham S, Xu Z, Hanson SM, Vishnivetskiy SA, Gurevich VV, Thibonnier M, Shoham M
(2006) Mol Pharmacol 70: 249-58
MeSH Terms: Amino Acid Sequence, Arrestins, Binding Sites, Binding, Competitive, Calmodulin, Carrier Proteins, Cobalt, Humans, Immunoblotting, Kinetics, Maltose-Binding Proteins, Models, Molecular, Molecular Sequence Data, Mutant Proteins, Mutation, Protein Binding, Receptors, Vasopressin, Recombinant Fusion Proteins, Solubility, Spectrometry, Fluorescence
Show Abstract · Added December 10, 2013
Signal transduction by G protein-coupled receptors (GPCRs) is mediated by interactions between intracellular proteins and exposed motifs on the cytoplasmic face of these receptors. Arrestins bind to GPCRs and modulate receptor function either by interfering with heterotrimeric G protein signaling or by serving as signaling adaptors themselves. Calmodulin interacts with GPCRs triggering a calcium response. We have studied the interaction of arrestin2 and calmodulin with intracellular elements of the human V1-vascular vasopressin receptor (hV1R). For this purpose, we designed, expressed, and purified soluble fusion proteins with the maltose-binding protein (MBP) from Escherichia coli that mimic the intracellular surface of the hV1R. These MBP fusion proteins bind arrestin2 and calmodulin with affinities in the micromolar range. A different series of soluble receptor analogs, named vasopressin receptor 1 elements on a soluble scaffold (V1ROSS) proteins, consist of the third intracellular loop and/or the C-terminal segment of the hV1R receptor juxtaposed on the surface of the MBP. V1ROSS proteins bind calmodulin and a truncated, phosphorylation-independent form of arrestin2 more tightly than the corresponding linear fusion proteins. Thus, embedding receptor loops within the three-dimensional structure of the MBP yields a better representation of the active conformation of these receptor loops than linear receptor peptides fused onto the C terminus of the MBP. V1ROSS proteins provide a valuable tool to study receptor interactions because they are more amenable to structural analysis than the native membrane receptor. These findings set the stage for the detailed structural analysis of these protein-protein interactions that are important for understanding the mechanism of signaling.
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20 MeSH Terms
Solution NMR spectroscopy of the human vasopressin V2 receptor, a G protein-coupled receptor.
Tian C, Breyer RM, Kim HJ, Karra MD, Friedman DB, Karpay A, Sanders CR
(2005) J Am Chem Soc 127: 8010-1
MeSH Terms: Escherichia coli, Humans, Nuclear Magnetic Resonance, Biomolecular, Protein Structure, Tertiary, Receptors, G-Protein-Coupled, Receptors, Vasopressin, Recombinant Proteins, Solutions
Show Abstract · Added December 21, 2013
The seven-transmembrane-spanning G protein-coupled receptor (GPCR) superfamily plays many important roles in basic biology, human health, and human disease. Here, well-resolved solution NMR spectra are presented for a human GPCR, the vasopressin V2 receptor in detergent micelles. The quality of the NMR spectra indicates that backbone resonance assignments for a majority of resonances are feasible. The key to obtaining high quality spectra appears to be the coupling of methods for expressing the receptor into membranes rather than into inclusion bodies, with use of a biochemically mild lysolipid detergent for membrane extraction, protein purification, and NMR sample preparation.
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8 MeSH Terms
Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality.
Ge Y, Ahn D, Stricklett PK, Hughes AK, Yanagisawa M, Verbalis JG, Kohan DE
(2005) Am J Physiol Renal Physiol 288: F912-20
MeSH Terms: Animals, Aquaporin 2, Aquaporins, Cyclic AMP, Deamino Arginine Vasopressin, Drinking, Endothelin-1, Integrases, Kidney Tubules, Collecting, Mice, Mice, Knockout, Osmolar Concentration, Promoter Regions, Genetic, Receptors, Vasopressin, Renal Agents, Urine, Vasopressins, Water, Water-Electrolyte Balance
Show Abstract · Added September 9, 2013
In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. CD ET-1 KO mice had impaired ability to excrete an acute, but not a chronic, water load, and this was associated with increased CD ET-1 mRNA in control, but not CD ET-1 KO, mice. In response to continuous infusion of 1-desamino-8-D-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.
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19 MeSH Terms
Calmodulin interacts with the V2 vasopressin receptor: elimination of binding to the C terminus also eliminates arginine vasopressin-stimulated elevation of intracellular calcium.
Nickols HH, Shah VN, Chazin WJ, Limbird LE
(2004) J Biol Chem 279: 46969-80
MeSH Terms: Amino Acid Sequence, Animals, Binding, Competitive, COS Cells, Calcium, Calmodulin, Cell Line, Cell Membrane, Cyclic AMP, DNA, Complementary, Detergents, Dogs, Dose-Response Relationship, Drug, Endocytosis, Enzyme-Linked Immunosorbent Assay, Glutathione Transferase, Humans, Hydrogen-Ion Concentration, Kinetics, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Peptides, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Receptors, Vasopressin, Sepharose, Sequence Homology, Amino Acid, Signal Transduction, Time Factors, Transfection, Two-Hybrid System Techniques, Vasopressins
Show Abstract · Added December 10, 2013
To identify molecules that might contribute to V2 vasopressin receptor (V2R) trafficking or signaling, we searched for novel interacting proteins with this receptor. Preliminary data, using the V2R C terminus as bait in a yeast two-hybrid screen, revealed calmodulin as a binding partner. Because calmodulin interacts with other G protein-coupled receptors, we explored this interaction and its possible functional relevance in greater detail. A Ca2+ -dependent interaction occurs between calmodulin-linked agarose and the holo-V2R as well as the V2R C terminus. Truncation and site-directed mutagenesis of the V2R C terminus revealed an involvement of an RGR sequence in this interaction. NMR studies showed that a peptide fragment of the V2R C terminus containing the RGR sequence binds to calmodulin in a Ca2+ -dependent manner with a Kd < or =1.5 microm; concentration-dependent binding of the V2R C terminus to calmodulin-agarose was used to estimate a Kd value of approximately 200 nm for this entire C-terminal sequence as expressed in mammalian cells. Madin-Darby canine kidney II cells stably expressing either wild type or a mutant V2R, in which the RGR C-terminal sequence was mutated to alanines (AAA V2R), revealed that the steady-state localization and agonist-induced internalization of the AAA V2R resembled that of the wild type V2R in polarized Madin-Darby canine kidney II cells. V2R binding of agonist similarly was unchanged in the AAA V2R, as was the concentration response for arginine vasopressin (AVP)-stimulated cAMP accumulation. Most interestingly, AVP-induced increases in intracellular Ca2+ observed for the wild type V2R were virtually eliminated for the AAA V2R. Taken together, the data suggest that a C-terminal region of the V2R important for calmodulin interaction is also important in modulation of V2R elevation of intracellular Ca2+, a prerequisite for AVP-induced fusion of aquaporin-containing vesicles with the apical surface of renal epithelial cells.
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33 MeSH Terms
Regulation of cyclooxygenase expression by vasopressin in rat renal medulla.
Zhang MZ, Sanchez Lopez P, McKanna JA, Harris RC
(2004) Endocrinology 145: 1402-9
MeSH Terms: Animals, Cyclooxygenase 1, Cyclooxygenase 2, Dinoprostone, Down-Regulation, Immunohistochemistry, In Vitro Techniques, Isoenzymes, Kidney Medulla, Male, Membrane Proteins, Osmolar Concentration, Prostaglandin-Endoperoxide Synthases, Rats, Rats, Brattleboro, Rats, Long-Evans, Receptors, Vasopressin, Up-Regulation, Vasopressins
Show Abstract · Added December 10, 2013
The antagonism between prostaglandin and vasopressin represents a classic negative feedback loop. It is not clear whether cyclooxygenase (COX)-2 and/or COX-1 expression is involved in elevated prostaglandin production stimulated by vasopressin in vivo. In the present study, we explored vasopressin regulation of medullary COX-2 and COX-1 expression acutely and chronically in rats. Medullary COX-1 expression was moderately lower and COX-2 expression was significantly lower in adult male Brattleboro rats than age-matched Long-Evans controls. Chronic treatment of Brattleboro rats with vasopressin for 1 wk led to a decrease in urine volume and a moderate increase in medullary COX-1; in contrast, medullary COX-2 expression was almost undetectable in untreated rats but was dramatically up-regulated with vasopressin treatment and was accompanied by increased urinary prostaglandin E(2) excretion. Further investigation revealed that both V1 and V2 receptors were involved in chronic medullary COX-1 and COX-2 up-regulation. Acute treatment with specific V1 or V2 receptor agonists resulted in specific increases in medullary COX-2, which was prevented by furosemide. Vasopressin did not affect COX-2 expression in cultured renomedullary interstitial cells. These data demonstrate that vasopressin stimulates medullary COX-2 expression through activation of both V1 and V2 receptors, and this stimulation is indirect and probably involves increased medullary electrolyte tonicity.
1 Communities
2 Members
1 Resources
19 MeSH Terms