A5051448461- Ion channel regulation and function
- Pain Mechanisms and Treatments
- Nicotinic Acetylcholine Receptors Study
- Cellular Mechanics and Interactions
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- Protist diversity and phylogeny
- Cardiac electrophysiology and arrhythmias
- Pharmacological Receptor Mechanisms and Effects
- Venomous Animal Envenomation and Studies
- Spaceflight effects on biology
- Viral Infectious Diseases and Gene Expression in Insects
- Insect Pest Control Strategies
- Legionella and Acanthamoeba research
- Insect and Pesticide Research
- Microtubule and mitosis dynamics
- Phenothiazines and Benzothiazines Synthesis and Activities
- Biocrusts and Microbial Ecology
- Monoclonal and Polyclonal Antibodies Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Coordination Chemistry and Organometallics
- Skin and Cellular Biology Research
- Hemoglobin structure and function
- Regulation of Appetite and Obesity
- Extracellular vesicles in disease
Emory University
2018
Merck & Co., Inc., Rahway, NJ, USA (United States)
1998-2013
Merck (Japan)
2004
Albert Einstein College of Medicine
1988-1990
The recently discovered growth hormone secretagogue, ghrelin, is a potent agonist at the human secretagogue receptor 1a (hGHSR1a). To elucidate structural features of this peptide necessary for efficient binding to and activation receptor, several analogues ghrelin with various aliphatic or aromatic groups in side chain residue 3, short peptides derived from were prepared tested assay an measuring intracellular calcium elevation HEK-293 cells expressing hGHSR1a. Bulky hydrophobic 3 turned...
Two peptides, ProTx-I and ProTx-II, from the venom of tarantula Thrixopelma pruriens, have been isolated characterized. These peptides were purified on basis their ability to reversibly inhibit tetrodotoxin-resistant Na channel, Na(V) 1.8, are shown belong inhibitory cystine knot (ICK) family peptide toxins interacting with voltage-gated ion channels. The has several hallmarks: bridge connectivity, mechanism channel inhibition, promiscuity across channels within families. connectivity...
Delayed-rectifier K+ currents (IDR) in pancreatic β-cells are thought to contribute action potential repolarization and thereby modulate insulin secretion. The voltage-gated channel, KV2.1, is expressed β-cells, the biophysical characteristics of heterologously channels similar those IDR rodent β-cells. A novel peptidyl inhibitor KV2.1/KV2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration ∼1 nmol/l), has been purified, characterized, used probe contribution these β-cell...
Voltage-gated calcium channel (Ca(v))2.2 (N-type channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious treating refractory pain but exhibits narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as...
A monomeric actin bundling protein with a native molecular weight of approximately 50,000 (ABP-50) has been isolated from amoebae Dictyostelium discoideum. ABP-50 cross-links F-actin to form tightly packed bundles, some which are highly ordered. It exhibits Kd 2.1 microM and molar ratio 1:1 in bundles. Calcium ATP at physiological concentrations have no effect on these activities. is immunologically unrelated 30-kDa protein, previously described Dictyostelium. Immunofluorescence...
Abstract Amoebae of the cellular slime mold Dictyostelium discoideum are an excellent model system for study amoeboid chemotaxis. These cells can be studied as a homogeneous population whose response to chemotactic stimulation is sufficiently synchronous permit correlation changes in cell shape and biochemical events during Having demonstrated this synchrony response, we show that actin polymerization occurs two stages with chemoattractants. The assembly F‐actin peaks between 40 60 sec after...
35S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized demonstrated to bind with high affinity a population receptors in Drosophila head membranes that previously shown be associated glutamate-gated chloride channel. Nodulisporic binding was modeled as single receptors. Ivermectin composed at least two kinetically distinct receptor populations, only one which binding. The these ligands modulated by glutamate, ivermectin, antagonists invertebrate...
Tryptic digestion of ABP-120, an actin cross-linking protein from Dictyostelium discoideum, generates a ladder peptides differing in molecular mass by 13,000 daltons, indicating structural repeat within the molecule. A number bind with smallest having 17,000 daltons (T17). Our sedimentation assays also show that peptide 14,000 does not actin. Using full-length cDNA sequence (Noegel, A., Rapp, S., Lottspeich, F., Schleicher, M., and Stewart, M. (1989) J. Cell Biol. 109, 607-618) sequencing...
Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca<sub>V</sub>2.2) as therapeutic targets chronic pain. A state-dependent Ca<sub>V</sub>2.2 inhibitor may an improved window over ziconotide, the peptidyl used clinically. Supporting this notion, we recently reported that in preclinical models, Ca<sub>V</sub>2 (3<i>R</i>)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1<i>H</i>-1,2,4-triazol-3-yl)-1,3-dihydro-2<i>H</i>-indol-2-one...
Abstract In this work we evaluate the cartical expansion model for amoeboid chemo‐taxis with regard to new information about molecular events in cytoskeleton following chemo‐tactic stimulation of Dictyostelium amoebae. A rapid upshift concentration chemoattrac‐tant can be used synchronize motile behavior a large population cells. This synchrony presents an opportunity study biochemical basis morphological changes such as pseudopod extension that are required chemotaxis. Changes composition...
The discovery of novel therapeutic agents that act on voltage-gated sodium channels requires the establishment high-capacity screening assays can reliably measure activity these proteins. Fluorescence resonance energy transfer (FRET) technology using membrane potential-sensitive dyes has been shown to provide a readout channel in stably transfected cell lines. Due inherent rapid inactivation channels, require presence activator prolong opening. Because activators and test compounds may share...
Actin polymerization occurs in amebae of Dictyostelium discoideum after chemotactic stimulation (Hall, A. L., Schlein, and J. Condeelis. 1988. Cell. Biochem. 37:285-299). When cells are lysed with Triton X-100 during stimulation, an actin nucleation activity is detected lysates by measuring the rate pyrene-labeled polymerization. This stimulated closely correlated observed vivo its kinetics, developmental regulation, cytochalasin D sensitivity. coordinate pseudopod extension synchronized...
Nodulisporic acid (NA) is an indole diterpene fungal product with insecticidal activity. NA activates a glutamate-gated chloride channel (GluCl) in grasshopper neurons and potentiates opening by glutamate. The endectocide ivermectin (IVM) induces similar, but larger current than NA. Using Drosophila melanogaster head membranes, high affinity binding site for was identified. Equilibrium studies show that amide analogue, N-(2-hydroxyethyl-2,2-3H)nodulisporamide ([3H]NAmide), binds to single...
Cav2.2 channels play a critical role in pain signaling by controlling synaptic transmission between dorsal root ganglion neurons and horn neurons. The Cav2.2-selective peptide blocker ziconotide (Prialt®, Elan Pharmaceuticals, Dublin, Ireland) has proven efficacious relief, but poor therapeutic index requires intrathecal administration. This provided impetus for finding an orally active, state-dependent inhibitor with improved safety profile. Members of the Cav2 subfamily calcium are main...
Triton-insoluble cytoskeletons were isolated from Dictyostelium discoideum AX3 cells prior to and following stimulation with 2'deoxy cyclic adenosine monophosphate (cAMP). Temporal changes in the content of actin a 120,000 dalton actin-binding protein (ABP-120) monitored. Both ABP-120 incorporated into cytoskeleton at 30-40 seconds stimulation, which is cotemporal onset pseudopod extension during amoebae chemoattractants. Changes total cytoskeletal myosin determined under same experimental...
The voltage-gated calcium channel Ca(v)2.2 (N-type channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment chronic pain. We report here discovery sulfonamide-derived, state-dependent inhibitors Ca(v)2.2. In particular, 19 inhibitor that selective over cardiac ion channels, with good preclinical PK biodistribution profile. This compound exhibits dose-dependent efficacy in models inflammatory hyperalgesia neuropathic allodynia devoid...
Extracellular vesicles (EVs) from bone marrow (BM)-derived mesenchymal stromal cells (BM-MSC) are novel mechanisms of cell-cell communication over short and long distances. BM-MSC have been shown to support human antibody secreting (ASC) survival ex vivo, but whether the crosstalk between MSC-ASC interaction can occur via EVs is not known. Thus, we evaluated role in ASC IgG secretion. were isolated irradiated non-irradiated primary quantified. They further characterized by electron...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTType III .omega.-Agatoxins: A Family of Probes for Similar Binding Sites on L- and N-Type Calcium ChannelsEric A. Ertel, Vivien Warren, Michael E. Adams, Patrick R. Griffin, Charles J. Cohen, McHardy M. SmithCite this: Biochemistry 1994, 33, 17, 5098–5108Publication Date (Print):May 1, 1994Publication History Published online1 May 2002Published inissue 1...