A5045259945- Ion channel regulation and function
- Ion Transport and Channel Regulation
- Nicotinic Acetylcholine Receptors Study
- Cardiac electrophysiology and arrhythmias
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Analytical Chemistry and Sensors
- Electrochemical Analysis and Applications
- Adenosine and Purinergic Signaling
- Advanced biosensing and bioanalysis techniques
- Chemical Synthesis and Analysis
- Mass Spectrometry Techniques and Applications
- RNA Interference and Gene Delivery
- Ion Channels and Receptors
- Neuroscience and Neural Engineering
- RNA and protein synthesis mechanisms
- Insect and Pesticide Research
- Biochemical Analysis and Sensing Techniques
- Neurobiology and Insect Physiology Research
- Advanced Chemical Sensor Technologies
- Renal function and acid-base balance
- Electrochemical sensors and biosensors
- Photoreceptor and optogenetics research
- Hearing, Cochlea, Tinnitus, Genetics
- Synthesis and Biological Evaluation
University of Copenhagen
2016-2025
University of Milan
2018
University of Bern
2018
University Hospital of Bern
2018
University of British Columbia
2010-2014
Therapeutics Clinical Research
2013
The University of Queensland
2007-2011
National Postdoctoral Association
2011
The sodium leak channel (NALCN) is essential for survival in mammals: NALCN mutations are life-threatening humans and knockout lethal mice. However, the basic functional pharmacological properties of have remained elusive. Here, we found that robust function heterologous systems requires co-expression UNC79, UNC80, FAM155A. resulting complex constitutively active conducts monovalent cations but blocked by physiological concentrations extracellular divalent cations. Our data support notion...
Abstract Retigabine is a recently approved anticonvulsant that acts by potentiating neuronal M-current generated KCNQ2–5 channels, interacting with conserved Trp residue in the channel pore domain. Using unnatural amino-acid mutagenesis, we subtly altered properties of this to reveal specific chemical interactions required for retigabine action. Introduction non-natural isosteric H-bond-deficient analogue abolishes potentiation, indicating effects rely strongly on formation H-bond Trp....
Increased extracellular proton concentrations during neurotransmission are converted to excitatory sodium influx by acid-sensing ion channels (ASICs). 10-fold sodium/potassium selectivity in ASICs has long been attributed a central constriction the channel pore, but experimental verification is lacking due sensitivity of this structure conventional manipulations. Here, we explored basis for incorporating unnatural amino acids into channel, engineering stoichiometry and performing free energy...
Voltage-gated potassium (Kv) channels enable efflux and membrane repolarization in excitable tissues. Many Kv undergo a progressive loss of ion conductance the presence prolonged voltage stimulus, termed slow inactivation, but atomic determinants that regulate kinetics this process remain obscure. Using combination synthetic amino acid analogs concatenated channel subunits we establish two H-bonds near extracellular surface endow with mechanism to time entry into inactivation: an...
Acid-sensing ion channels (ASICs) are proton-gated broadly expressed in the vertebrate nervous system, converting decreased extracellular pH into excitatory sodium current. ASICs were previously thought to be a vertebrate-specific branch of DEG/ENaC family, conserved but functionally diverse family channels. Here, we provide phylogenetic and experimental evidence that throughout deuterostome animals, showing evolved over 600 million years ago. We also ASIC expression central system tunicate,...
Models describing the structural changes mediating Cys loop receptor activation generally give little attention to possibility that different agonists may promote via distinct M2 pore-lining domain rearrangements. We investigated this question by comparing effects of ligands on conformation external portion homomeric alpha1 glycine domain. Conformational flexibility was assessed tethering a rhodamine fluorophore cysteines introduced at 19' or 22' positions and monitoring fluorescence current...
Understanding the activation mechanism of Cys loop ion channel receptors is key to understanding their physiological and pharmacological properties under normal pathological conditions. The ligand-binding domains these comprise inner outer beta-sheets structural studies indicate that opening accompanied by conformational rearrangements in both beta-sheets. In an attempt resolve ligand-dependent movements domain, we employed voltage-clamp fluorometry on alpha1 glycine compare changes mediated...
Cys-loop receptor binding sites characteristically contain many aromatic amino acids. In nicotinic ACh and 5-HT 3 receptors, a Trp residue forms cation-π interaction with the agonist, whereas in GABA A Tyr performs this role. The glycine site, however, contains predominantly Phe residues. Homology models suggest that two of these side chains, Phe159 Phe207, possibly third, Phe63, are positioned such they could contribute to primary amine glycine. Here, we test hypothesis by incorporation...
Retigabine (RTG) is a first-in-class antiepileptic drug that suppresses neuronal excitability through the activation of voltage-gated KCNQ2-5 potassium channels. binds to pore-forming domain, causing hyperpolarizing shift in voltage dependence channel activation. To elucidate how retigabine binding site coupled changes sensing, we used voltage-clamp fluorometry track conformational KCNQ3 voltage-sensing domains (VSDs) response voltage, retigabine, and PIP2. Steady-state ionic conductance...
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...
The sodium (Na + ) leak channel (NALCN) is a member of the four-domain voltage-gated cation family that includes prototypical and calcium channels V s Ca s, respectively). Unlike Na which have four lateral fenestrations serve as routes for lipophilic compounds to enter central cavity modulate function, NALCN has bulky residues (W311, L588, M1145, Y1436) block these openings. Structural data suggest occluded underlie pharmacological resistance NALCN, but functional evidence lacking. To test...