A5065063896- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Nicotinic Acetylcholine Receptors Study
- Viral Infections and Outbreaks Research
- Immune Cell Function and Interaction
- Pain Mechanisms and Treatments
- Viral Infections and Vectors
- T-cell and B-cell Immunology
- Aldose Reductase and Taurine
- Neurobiology and Insect Physiology Research
- Viral gastroenteritis research and epidemiology
- Disaster Response and Management
- Mass Spectrometry Techniques and Applications
- Influenza Virus Research Studies
- Cancer-related Molecular Pathways
- Transport and Economic Policies
- Biochemical effects in animals
- Memory and Neural Mechanisms
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Mitochondrial Function and Pathology
- Cardiac Ischemia and Reperfusion
- Photosynthetic Processes and Mechanisms
- HER2/EGFR in Cancer Research
- Protein Structure and Dynamics
Arisan Therapeutics (United States)
2014-2022
Pfizer (United States)
2013
Durham University
2009
Vertex Pharmaceuticals (United States)
2006
University of Wisconsin–Madison
1996-2002
Aptose Biosciences (Canada)
2002
Ventana Research Corporation (United States)
1999
University of California, Berkeley
1995
Max Planck Institute of Experimental Medicine
1994-1995
Max Planck Institute for Biophysical Chemistry
1994
The high sensitivity of voltage-gated ion channels to changes in membrane potential implies that the process channel opening is accompanied by large charge movements. Previous estimates total displacement, q , have been deduced from voltage dependence activation and ranged 4 8 elementary charges (e 0 ). A more direct measurement Drosophila melanogaster Shaker 29-4 potassium yields a value 12.3 e . similar obtained mutated having reduced sensitivity. These results can be explained model for...
Significance Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve muscle cells. Because Na channel isoforms exhibit tissue-specific expression, subtype selective modulation of this family provides important drug development opportunities. However, most available modulators are unable distinguish between subtypes, which limits their therapeutic utility because cardiac or nervous system toxicity. This study describes a new class...
A leucine heptad repeat is well conserved in voltage-dependent ion channels. Herein we examine the role of region Shaker K+ channels through substitution leucines and coexpression normal truncated products. In contrast to leucine-zipper DNA-binding proteins, find that subunit assembly does not depend on repeat. Instead, report substitutions produce large effects observed voltage dependence conductance prepulse inactivation curves. Our results suggest mediate interactions play an important...
Mammalian voltage-activated Shaker K+ channels associate with at least three cytoplasmic proteins: Kv beta 1, 2 and 3. These subunits contain variable N-termini, which can modulate the inactivation of alpha subunits, but are homologous throughout an aldo-keto reductase core. Human ferret 3 proteins identical rat 1 core while not; also contains a shorter N-terminus has no reported physiological role. We report that human derived from same gene modulates properties Kv1.4 subunits.
A large number of related genes (the Sh gene family) encode potassium channel subunits which form voltage-dependent K+ channels by aggregating into homomultimers. One these genes, the Shaker in Drosophila, generates several products alternative splicing. These proteins with a constant central region flanked variable amino and carboxyl domains. Coinjection two RNAs different or ends Xenopus oocytes produces currents that display functional properties distinct from those observed when each RNA...
Shaker K+ channels are multimeric, probably tetrameric proteins. Substitution of a conserved leucine residue to valine (V2) at position 370 in the Drosophila 29-4 sequence results large alterations voltage dependence gating expressed channels. In order determine effects this mutation hybrid with fixed stoichiometry V2 and wild-type (WT) subunits we generated cDNA constructs two linked-monomeric similar tandem previously reported by Isacoff, E. Y., Y. N. Jan, L. Jan. (1990. Nature (Lond.)....
Kvβ2 binds to K+ channel α subunits from at least two different families (Kv1 and Kv4) is a member of the aldo-ketoreductase (AKR) superfamily. Proposed functions for this protein in vivo include chaperone-like role Kv1 subunit biogenesis catalytic activity as an AKR oxidoreductase. To investigate function Kvβ2, Kvβ2-null point mutant (Y90F) mice were generated through gene targeting embryonic stem cells. In mice, Kv1.1 Kv1.2 localize normally cerebellar basket cell terminals juxtaparanodal...
We identified and explored the structure–activity-relationship (SAR) of an adamantane carboxamide chemical series Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC50 values) ∼10–15 nM in vesicular stomatitis (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC50 activity against wild type EBOV, aqueous solubility >20 mg/mL, attractive metabolic stability human nonhuman liver microsomes. X-ray cocrystallographic...
A leucine residue at position 370 (L370) in 29-4 Shaker K+ channels resides within two overlapping sequence motifs conserved among most voltage-gated channels: the S4 segment and a heptad repeat. Here we investigate effects observed upon substitution of L370 with many other uncharged amino acid residues. We find that smaller or more hydrophilic residues produce greater alterations both activation inactivation gating than does large hydrophobic In addition, subunits containing less...
Shaker-type potassium (K+) channels are composed of pore-forming alpha subunits associated with cytoplasmic beta subunits. Kv beta2 is the predominant subunit in mammalian nervous system, but its functions vivo not clear. beta2-null mice have been previously characterized our laboratory as having reduced lifespans, cold swim-induced tremors and occasional seizures, no apparent defect alpha-subunit trafficking. To test whether strain differences might influence severity this phenotype, we...
Food avoidance learning in the mollusc Pleurobranchaea entails reduction responsiveness of key brain interneurons feeding neural circuitry, paracerebral command (PCNs), to neurotransmitter acetylcholine (AcCho). stimuli applied oral veil an untrained animal depolarize PCNs and induce motor program (FMP). Atropine (a muscarinic cholinergic antagonist) reversibly blocks food-induced depolarization PCNs, implicating AcCho as mediating food detection. directly PCN somata depolarizes them,...
Influenza A viruses cause the respiratory illness influenza, which can be mild to fatal depending on strain and host immune response. The flu polymerase acidic (PA), basic 1 (PB1) 2 (PB2) proteins comprise RNA-dependent RNA complex responsible for viral genome replication. first crystal structures of C-terminal domain PA (PA-CTD) in absence PB1-derived peptides show a number structural changes relative previously reported PB1-peptide bound structures. human A/WSN/1933 (H1N1) avian...
Introduction In Part II of this trilogy, I investigate the extent to which current basic science can be applied development novel entities with potential for entering preclinical evaluation. Following on from treatment in I, explore greater depth role cholecystokinin (CCK) as an anti-opioid peptide. A re-evaluation earlier studies confirms important selective antagonists CCKB receptor subtype co-analgesics morphine patients intractable pain.1–3 attempting unravel mechanisms whereby CCK...