Augmented axonal defects and synaptic degenerative changes in female GRK5 deficient mice.
AuthorsLi L, Rasul I, Liu J, Zhao B, Tang R, Premont RT, Suo WZ
JournalBrain Res Bull
PubMed ID18955119
'Recent studies suggested that G protein-coupled receptor kinase 5 (GRK5) deficiency plays a significant role in early Alzheimer''s disease (AD) pathogenesis, and that the GRK5 knockout (GRK5KO) mouse displays an early Alzheimer-like cognitive deficit associated with increased hippocampal axonal defects and synaptic degenerative changes. Gender is known to play a ... More
A small molecule inverse agonist for the human thyroid-stimulating hormone receptor.
AuthorsNeumann S, Huang W, Eliseeva E, Titus S, Thomas CJ, Gershengorn MC
JournalEndocrinology
PubMed ID20427476
'Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe ... More
A homogeneous enzyme fragment complementation-based beta-arrestin translocation assay for high-throughput screening of G-protein-coupled receptors.
AuthorsZhao X, Jones A, Olson KR, Peng K, Wehrman T, Park A, Mallari R, Nebalasca D, Young SW, Xiao SH
JournalJ Biomol Screen
PubMed ID18660457
'G-protein-coupled receptors (GPCRs) represent one of the largest gene families in the human genome and have long been regarded as valuable targets for small-molecule drugs. The authors describe a new functional assay that directly monitors GPCR activation. It is based on the interaction between beta-arrestin and ligand-activated GPCRs and uses ... More
Tumor necrosis factor (TNF)-soluble high-affinity receptor complex as a TNF antagonist.
AuthorsMcKenna SD, Feger G, Kelton C, Yang M, Ardissone V, Cirillo R, Vitte PA, Jiang X, Campbell RK
JournalJ Pharmacol Exp Ther
PubMed ID17495128
'A novel high-affinity inhibitor of tumor necrosis factor (TNF) is described, which is created by the fusion of the extracellular domains of TNF-binding protein 1 (TBP-1) to both the alpha and beta chains of an inactive version of the heterodimeric protein hormone, human chorionic gonadotropin. The resulting molecule, termed TNF-soluble ... More
Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling.
AuthorsAllen MD, Neumann S, Gershengorn MC
JournalFASEB J
PubMed ID21705666
'The thyroid-stimulating hormone (TSH) receptor signals via G(s) to produce cAMP and via G(q/11) to produce inositol-1,4,5-trisphosphate, which is degraded to inositol monophosphate (IP1; phosphoinositide signaling). The potency of TSH for cAMP signaling is higher than for phosphoinositide signaling, and it was suggested that there are "spare receptors" for cAMP ... More
Characterization and expression of the short neuropeptide F receptor in the African malaria mosquito, Anopheles gambiae.
AuthorsGarczynski SF, Crim JW, Brown MR
JournalPeptides
PubMed ID17140700
'A short neuropeptide F (sNPF) precursor and a sNPF receptor (sNPFR) were characterized for the mosquito, Anopheles gambiae. The sNPFR was expressed in CHO-K1 cells, and it exhibited high affinity binding, IC(50) approximately 3-5 nM, for specific sNPFs. sNPF1 potently inhibited forskolin-stimulated cAMP production by transfected cells, suggesting sNPFR acts ... More
RTP family members induce functional expression of mammalian odorant receptors.
AuthorsSaito H, Kubota M, Roberts RW, Chi Q, Matsunami H
JournalCell
PubMed ID15550249
'Transport of G protein-coupled receptors (GPCRs) to the cell surface membrane is critical in order for the receptors to recognize their ligands. However, mammalian GPCR odorant receptors (ORs), when heterologously expressed in cells, are poorly expressed on the cell surface. Here we show that the transmembrane proteins RTP1 and RTP2 ... More
A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor.
AuthorsNeumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C, Monaco F, Huang W, Gershengorn MC
JournalJ Clin Endocrinol Metab
PubMed ID21123444
Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor (TSHR). We previously reported the first small-molecule antagonist of human TSHR and showed that it inhibited receptor signaling stimulated by sera from four patients with GD. ... More
A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers.
AuthorsSubramanian GM, Cronin PW, Poley G, Weinstein A, Stoughton SM, Zhong J, Ou Y, Zmuda JF, Osborn BL, Freimuth WW
JournalClin Infect Dis
PubMed ID15937757
Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational ... More
The Synthesis and Evaluation of Dihydroquinazolin-4-ones and Quinazolin-4-ones as Thyroid Stimulating Hormone Receptor Agonists.
AuthorsEnglund EE, Neumann S, Eliseeva E, McCoy JG, Titus S, Zheng W, Southall N, Shin P, Leister W, Thomas CJ, Inglese J, Austin CP, Gershengorn MC, Huang W
JournalMedchemcomm
PubMed ID22408719
We herein describe the rapid synthesis of a diverse set of dihydroquinazolin-4-ones and quinazolin-4-ones, their biological evaluation as thyroid stimulating hormone receptor (TSHR) agonists, and SAR analysis. Among the compounds screened, 8b was 60-fold more potent than the hit compound 1a, which was identified from a high throughput screen of ... More
Production of biologically active Bacillus anthracis edema factor in Escherichia coli.
Anthrax is caused by the gram-positive spore-forming bacterium Bacillus anthracis. The anthrax toxin consists of three proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF). PA facilitates the translocation of LF and EF into the cytosol of mammalian cells. LF is thought to be a zinc-dependent metalloprotease that ... More
Development of an edema factor-mediated cAMP-induction bioassay for detecting antibody-mediated neutralization of anthrax protective antigen.
AuthorsZmuda JF, Zhang L, Richards T, Pham Q, Zukauskas D, Pierre JL, Laird MW, Askins J, Choi GH
JournalJ Immunol Methods
PubMed ID15847796
Intoxication of mammalian cells by Bacillus anthracis requires the coordinate activity of three distinct bacterial proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). Among these proteins, PA has become the major focus of work on monoclonal antibodies and vaccines designed to treat or prevent anthrax infection since ... More
Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function.
AuthorsPark S, Dong X, Fisher TL, Dunn S, Omer AK, Weir G, White MF
JournalJ Biol Chem
PubMed ID16272563
The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes beta cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon beta cells in rodents and ... More
Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts.
AuthorsZhong H, Belardinelli L, Maa T, Zeng D
JournalAm J Respir Cell Mol Biol
PubMed ID15472138
Chronic inflammatory airway diseases, such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis, are associated with subepithelial fibroblast activation, myofibroblast hyperplasia, hypoxia, and increase in interstitial adenosine concentrations. The goal of this study was to determine the effect of adenosine and its receptors on activation of human lung fibroblasts ... More
Biological properties of a novel follicle-stimulating hormone/human chorionic gonadotropin chimeric gonadotropin.
AuthorsGarone LM, Ammannati E, Brush TS, Fischer DJ, Tos EG, Luo J, Altobello KL, Ciampolillo C, Ihley TM, Kurosawa E, Tiebout A, McKenna S
JournalEndocrinology
PubMed ID16794004
A chimeric recombinant human gonadotropin, termed C3, demonstrates both follitropic and lutropic bioactivities. The alpha-subunit construct for C3 is comprised of the recombinant wild-type human glycoprotein hormone alpha-subunit. The beta-subunit DNA construct for C3 encodes residues 1-145 from human chorionic gonadotropin (hCG)-beta with the exceptions that FSH beta amino acid ... More
Persistent cAMP signaling by thyrotropin (TSH) receptors is not dependent on internalization.
AuthorsNeumann S, Geras-Raaka E, Marcus-Samuels B, Gershengorn MC
JournalFASEB J
PubMed ID20538910
Evidence was presented that thyrotropin [thyroid-stimulating hormone (TSH)]-stimulated persistent cAMP signaling is dependent on receptor (with G-protein a subunits and adenylyl cyclase) internalization. Because it is not clear whether G proteins and adenylyl cyclase internalize with receptors, we tested whether persistent cAMP signaling by TSH receptor (TSHR) is dependent on ... More
A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase.
AuthorsZhong H, Wu Y, Belardinelli L, Zeng D
JournalAm J Respir Cell Mol Biol
PubMed ID16778150
Adenosine is a signaling nucleoside that has been proposed to contribute to the pathogenesis of asthma and chronic obstructive pulmonary disease. Previous studies suggest that adenosine might play an important role in modulating levels of inflammatory mediators in the lung. Because airway epithelium is an important cellular source of inflammatory ... More
Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury.
AuthorsSun CX, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, Belardinelli L, Zeng D, Blackburn MR
JournalJ Clin Invest
PubMed ID16841096
Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these ... More
Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor.
AuthorsKleinau G, Haas AK, Neumann S, Worth CL, Hoyer I, Furkert J, Rutz C, Gershengorn MC, Schülein R, Krause G
JournalFASEB J
PubMed ID20179143
The thyrotropin receptor [thyroid-stimulating hormone receptor (TSHR)], a G-protein-coupled receptor (GPCR), is endogenously activated by thyrotropin, which binds to the extracellular region of the receptor. We previously identified a low-molecular-weight (LMW) agonist of the TSHR and predicted its allosteric binding pocket within the receptor's transmembrane domain. Because binding of the ... More
AuthorsBoutin A, Allen MD, Geras-Raaka E, Huang W, Neumann S, Gershengorn MC
JournalMol Pharmacol
PubMed ID21525174
The thyrotropin [thyroid-stimulating hormone (TSH)] receptor (TSHR) is known to acutely and persistently stimulate cAMP signaling and at higher TSH concentrations to acutely stimulate phosphoinositide signaling. We measured persistent signaling by stimulating TSHR-expressing human embryonic kidney-EM293 cells with TSH and measuring cAMP or inositol monophosphate (IP1) production, a measure of ... More