A5008484908- Ion channel regulation and function
- Receptor Mechanisms and Signaling
- Nicotinic Acetylcholine Receptors Study
- Neuroscience and Neuropharmacology Research
- Electrochemical Analysis and Applications
- Lipid Membrane Structure and Behavior
- Analytical Chemistry and Chromatography
- Ion Channels and Receptors
- Cardiac electrophysiology and arrhythmias
- Chemical Synthesis and Analysis
- Photoreceptor and optogenetics research
- Electron Spin Resonance Studies
- Mass Spectrometry Techniques and Applications
- Molecular Sensors and Ion Detection
- Neurotransmitter Receptor Influence on Behavior
- Phenothiazines and Benzothiazines Synthesis and Activities
- Chemical synthesis and alkaloids
- Nanopore and Nanochannel Transport Studies
- Fluorine in Organic Chemistry
- Herbal Medicine Research Studies
- Chemical Reactions and Isotopes
- Fault Detection and Control Systems
- Cannabis and Cannabinoid Research
- RNA and protein synthesis mechanisms
- Photosynthetic Processes and Mechanisms
Case Western Reserve University
2015-2024
Kent State University
2016
University School
2014-2016
Institute of Molecular Biology and Biophysics
2015
Center for Neurosciences
2015
University of Chicago
2007-2011
Texas Tech University
2010
University of Illinois Chicago
2009
University at Buffalo, State University of New York
2003-2004
Abstract Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington’s disease (HD) by evoking defects the mitochondria, but underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding on mitochondria. Here we show that VCP is selectively translocated to where it bound mtHtt various HD models. Mitochondria-accumulated elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction...
Abstract Serotonin receptors (5-HT 3A R) directly regulate gut movement, and drugs that inhibit 5-HT R function are used to control emetic reflexes associated with gastrointestinal pathologies cancer therapies. The involves a finely tuned orchestration of three domain movements include the ligand-binding domain, pore intracellular domain. Here, we present structure from full-length channel in apo-state determined by single-particle cryo-electron microscopy at nominal resolution 4.3 Å. In...
Abstract Glycinergic synapses play a central role in motor control and pain processing the nervous system. Glycine receptors (GlyRs) are key players mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into molecular architecture of GlyR, several mechanistic questions pertaining to channel function still unanswered. Here, we present Cryo-EM full-length GlyR protein complex reconstituted lipid nanodiscs that captured...
Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination sensory perception. Synaptic GlyRs are a heteromeric assembly of α β subunits. Here we present cryo-EM structures full-length zebrafish α1βBGlyR presence an antagonist (strychnine), agonist (glycine), or with positive allosteric modulator (glycine/ivermectin). Each structure shows distinct pore conformation varying degrees asymmetry. Molecular dynamic...
We used single-channel recording and model-based kinetic analyses to quantify the effects of mutations in extracellular domain (ECD) alpha-subunit mouse muscle-type acetylcholine receptors (AChRs). The crystal structure an binding protein (AChBP) suggests that ECD is comprised a beta-sandwich core surrounded by loops. Here we focus on loops 2 7, which lie at interface AChR transmembrane domains. Side chain substitutions these primarily affect channel gating either decreasing or increasing...
The prokaryotic K+ channel KcsA is activated by intracellular protons and its gating modulated transmembrane voltage. Typically, functions have been studied under steady-state conditions, using macroscopic Rb+-flux experiments single-channel current measurements. These studies provided limited insights into the kinetics of due to low open probability, uncertainties in number channels patch, a very strong intrinsic kinetic variability. In this work, we carried out detailed analysis...
Desensitization in pentameric ligand-gated ion channels plays an important role regulating neuronal excitability. Here, we show that docosahexaenoic acid (DHA), a key ω−3 polyunsaturated fatty synaptic membranes, enhances the agonist-induced transition to desensitized state prokaryotic channel GLIC. We determined 3.25 Å crystal structure of GLIC-DHA complex potentially conformation. The DHA molecule is bound at channel-periphery near M4 helix and exerts long-range allosteric effect on pore...
Abstract Serotonin receptor (5-HT 3A R) is the most common therapeutic target to manage nausea and vomiting during cancer therapies in treatment of irritable bowel syndrome. Setrons, a class competitive antagonists, cause functional inhibition 5-HT R gastrointestinal tract brainstem, acting as effective anti-emetic agents. Despite their prevalent use, molecular mechanisms underlying setron binding are not fully understood. Here, we present structure granisetron-bound full-length solved by...
The kinetic transitions of proton-activated WT KcsA and the noninactivating E71A mutant were studied at single-channel level in purified, liposome-reconstituted preparations. Single-channel currents recorded using patch-clamp techniques under nonstationary steady-state conditions. Maximum-likelihood analyses reveal that key influence acidic pH is to increase frequency bursting without an effect on intraburst open closed dwell times, consistent with finding from macroscopic protons promote...
Crystal structures of Gloeobacter violaceus ligand-gated ion channel (GLIC), a proton-gated prokaryotic homologue pentameric (LGIC) from G. violaceus, have provided high-resolution models the architecture and its role in selective conduction drug binding. However, it is still unclear which functional states LGIC gating scheme these crystal represent. Much this uncertainty arises lack thorough understanding properties channels. To elucidate molecular events that constitute gating, we carried...
Serotonin receptors (5-HT 3A R) play a crucial role in regulating gut movement, and are the principal target of setrons, class high-affinity competitive antagonists, used management nausea vomiting associated with radiation chemotherapies. Structural insights into setron-binding poses their inhibitory mechanisms just beginning to emerge. Here, we present high-resolution cryo-EM structures full-length 5-HT R complex palonosetron, ondansetron, alosetron. Molecular dynamic simulations these...
Neuromuscular acetylcholine receptors are synaptic ion channels that open and close with rate constants of approximately equal to 48,000 s(-1) 1,700 s(-1), respectively (in adult mouse, at 24 degrees C, -100 mV membrane potential). Perturbations many different sites in the protein can change these constants, those extracellular domain mainly affecting channel-opening intracellular domains channel-closing. We used single-channel recordings measure total time per activation (tau(b)) elicited...
Direct structural insights on the fundamental mechanisms of permeation, selectivity, and gating remain unavailable for Na(+) Ca(2+) channel families. Here, we report spectroscopic characterization isolated Voltage-Sensor Domain (VSD) prokaryotic NaChBac in a lipid bilayer. Site-directed spin-labeling EPR spectroscopy were carried out 118 mutants covering all VSD. environmental data used to unambiguously assign secondary structure elements, define membrane insertion limits, evaluate activated...
Direct structural insight into the mechanisms underlying activation and desensitization remain unavailable for pentameric ligand-gated channel family. Here, we report rearrangements gating transitions in membrane-embedded GLIC, a prokaryotic homologue, using site-directed spin labeling electron paramagnetic resonance (EPR) spectroscopy. We particularly probed conformation of pore-lining second transmembrane segment (M2) under conditions that favor closed ligand-bound desensitized states. The...