A5054894589- Ion channel regulation and function
- Nicotinic Acetylcholine Receptors Study
- Ion Transport and Channel Regulation
- Receptor Mechanisms and Signaling
- Electrochemical Analysis and Applications
- Neuroscience and Neuropharmacology Research
- Mass Spectrometry Techniques and Applications
- Renal function and acid-base balance
- Analytical Chemistry and Sensors
- Photoreceptor and optogenetics research
- Ion Channels and Receptors
- Cholinesterase and Neurodegenerative Diseases
- Hormonal Regulation and Hypertension
- Marine Toxins and Detection Methods
- Aldose Reductase and Taurine
- Neurobiology and Insect Physiology Research
- Nitric Oxide and Endothelin Effects
- Lipid Membrane Structure and Behavior
- Chemical synthesis and alkaloids
- Phenothiazines and Benzothiazines Synthesis and Activities
- Computational Drug Discovery Methods
- Fuel Cells and Related Materials
- Neuroendocrine regulation and behavior
- Spectroscopy and Quantum Chemical Studies
- Vascular Malformations Diagnosis and Treatment
University of Copenhagen
2019-2024
Science for Life Laboratory
2013-2021
Stockholm University
2013-2021
KTH Royal Institute of Technology
2013-2015
École Polytechnique Fédérale de Lausanne
2013
The University of Texas at Austin
2013
Acid-sensing ion channels (ASICs) are proton-gated cation that contribute to neurotransmission, as well initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the vivo regulation ASICs, especially by endogenous neuropeptides potently modulate ASICs. The most potent ASIC modulator known date opioid neuropeptide big dynorphin (BigDyn). BigDyn up-regulated chronic increases ASIC-mediated during acidosis. Understanding mechanism site...
Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation inhibition in pentameric ligand-gated ion channels, but detailed structural mechanism these bimodal effects lacking. The prokaryotic model protein GLIC recapitulates anesthetic human it accessible to structure determination apparent open closed states. Here, we report ten X-ray...
Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due limited structural data simulation timescales. Here, we used enhanced sampling simulate pH-gated channel GLIC, construct Markov state models (MSMs) gating. Consistent with new functional recordings, report oocytes, our analysis revealed differential effects protonation mutation on...
Unlike classical voltage-gated sodium (NaV) channels, NaX has been characterized as a voltage-insensitive, tetrodotoxin-resistant, (Na+)-activated channel involved in regulating Na+ homeostasis. However, remains refractory to functional characterization traditional heterologous systems. Here, gain insight into its atypical physiology, we determine structures of the human complex with auxiliary β3-subunit. reveals structural alterations within selectivity filter, voltage sensor-like domains,...
Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes pentameric ligand-gated ion channels; however, structures physiologically relevant proteins this family yet define anesthetic binding at high resolution. Recent cocrystal the bacterial protein GLIC provide snapshots state-dependent sites for common surgical agent propofol (PFL), offering a detailed model system modulation....
GABA<sub>A</sub> receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure anesthetic propofol bound to <i>Gloeobacter violaceus</i> ligand-gated ion channel (GLIC), bacterial homolog receptors, provided an opportunity explore structure-based ligand discovery for pentameric channels (pLGICs). We used molecular docking 153,000 commercially available compounds identify molecules that interact with binding site GLIC. In total, 29 were selected...
Acid-sensing ion channels (ASICs) are trimeric proton-gated cation involved in fast synaptic transmission. Pharmacological inhibition of ASIC1a reduces neurotoxicity and stroke infarct volumes, with the cysteine knot toxin psalmotoxin-1 (PcTx1) being one most potent selective inhibitors. PcTx1 binds at subunit interface extracellular domain (ECD), but mechanism conformational consequences interaction, as well number molecules required for inhibition, remain unknown. Here, we use...
The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, anticonvulsants. However, the mechanisms channel opening, gating, modulation these leave many open questions, despite their pharmacological importance. Subtle conformational changes both extracellular transmembrane domains likely to influence but have been difficult...
Abstract Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling neurons and other excitable cells. For many the mechanistic details of gating remain unclear, partly due limited structural data simulation timescales. Here, we used enhanced sampling simulate pH-gated channel GLIC, construct Markov state models (MSMs) transitions. Consistent with new functional recordings reported here oocytes, our analysis revealed differential effects...
ABSTRACT Acid-sensing ion channels (ASICs) are trimeric that open a cation-conducting pore in response to proton binding. Excessive ASIC activation during prolonged acidosis conditions such as inflammation and ischemia is linked pain stroke. A conserved lysine the extracellular domain (Lys211 mASIC1a) suggested play key role function. However, precise contributions difficult dissect with conventional mutagenesis, replacement of Lys211 naturally occurring amino acids invariably changes...
Summary Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception synaptic plasticity. ASIC1a is the most abundant subunit in central nervous system forms homomeric permeable Na + Ca 2+ , making it a compelling therapeutic target for acidotic pathologies including stroke traumatic brain injury. However, complete conformational library of human its various functional states has yet be described. Using cryo-EM, we obtained hASIC1a structures...
Abstract Acid-sensing ion channels (ASICs) are proton-gated cation that contribute to neurotransmission, as well initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the vivo regulation ASICs, especially by endogenous neuropeptides potently modulate ASICs. The most potent ASIC modulator known date opioid neuropeptide big dynorphin (BigDyn). BigDyn upregulated chronic increases ASIC-mediated during acidosis. Understanding...
Pentameric ligand-gated ion channels are heavily implicated in neurological effects of alcohol, yet high-resolution structural data this family receptors limited. The prokaryotic channel GLIC is a potentially valuable model system whose structure …
Abstract Acid-sensing ion channels (ASICs) are proton-gated cation that contribute to fast synaptic transmission and have roles in fear conditioning nociception. Apart from activation at low pH, ASIC1a also undergoes several types of desensitization, including ‘acute desensitization’ terminates activation, ‘steady-stated occurs sub-activating proton concentrations limits subsequent ‘tachyphylaxis’ results a progressive decrease response during series activations. Structural insights...