A5030564148- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Cardiac Ischemia and Reperfusion
- Ion Transport and Channel Regulation
- Neuroscience and Neural Engineering
- Receptor Mechanisms and Signaling
- Ion Channels and Receptors
- Lipid Membrane Structure and Behavior
- Fuel Cells and Related Materials
- Nicotinic Acetylcholine Receptors Study
- Anesthesia and Neurotoxicity Research
- Nanopore and Nanochannel Transport Studies
- Advanced Memory and Neural Computing
- Calcium signaling and nucleotide metabolism
- Analytical Chemistry and Sensors
- Electrochemical Analysis and Applications
- Coordination Chemistry and Organometallics
- Advanced biosensing and bioanalysis techniques
- Mass Spectrometry Techniques and Applications
- RNA and protein synthesis mechanisms
- Signaling Pathways in Disease
- Hearing, Cochlea, Tinnitus, Genetics
- Phosphodiesterase function and regulation
- Adenosine and Purinergic Signaling
Kiel University
2016-2025
Czech Academy of Sciences, Institute of Physiology
2018
Physiological Society
2012-2014
Friedrich Schiller University Jena
2003-2010
Center for Clinical Studies
2010
Jena University Hospital
2010
Schiller International University
2007
University of Freiburg
2004
University of Tübingen
1998-2001
Massachusetts General Hospital
1995-1996
Adenosine triphosphate (ATP)–sensitive potassium (K ATP ) channels couple electrical activity to cellular metabolism through their inhibition by intracellular ATP. of K varies among tissues and is affected the metabolic regulatory state individual cells, suggesting involvement endogenous factors. It reported here that phosphatidylinositol-4,5-bisphosphate (PIP 2 phosphatidylinositol-4-phosphate (PIP) controlled cloned ir 6.2 SUR1). These phospholipids acted on subunit shifted sensitivity...
Two-pore domain (K2P) K(+) channels are major regulators of excitability that endow cells with an outwardly rectifying background "leak" conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show gating is common to most and this voltage sensitivity originates from movement three four ions into high electric field inactive selectivity filter. Overall,...
Voltage-gated potassium (Kv) channels control action potential repolarization, interspike membrane potential, and frequency in excitable cells. It is thought that the combinatorial association between distinct alpha beta subunits determines whether Kv function as non-inactivating delayed rectifiers or rapidly inactivating A-type channels. We show lipids can convert into vice versa. Phosphoinositides remove N-type inactivation from by immobilizing domains. Conversely, arachidonic acid its...
Quaternary ammonium blockers inhibit many voltage-activated potassium (K+) channels from the intracellular side. When applied to Drosophila Shaker expressed in mammalian cells, these rapidly reversible produced use-dependent inhibition through an unusual mechanism--they promoted intrinsic conformational change known as C-type inactivation, which recovery is slow. The did so by cutting off ion flow a site pore, then emptied at rate of 10(5) ions per second. This slow probably reflected...
Mutations of the KCNJ10 ( Kir4.1 ) K + channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated localization homologous KCNJ16 in kidney functional consequences mutations found our patients with EAST Kcnj10 Kcnj16 were basolateral membrane mouse distal convoluted tubules, connecting cortical collecting ducts. In human kidney, staining was additionally observed thick ascending limb Henle's loop. EM...
A key to potassium channel activation Using drugs activate channels has the potential treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with defined pharmacore that use similar mechanism many types channels. X-ray crystallography, functional analysis, molecular dynamics simulations showed NCAs bind below selectivity filter open gate Targeting this NCA site might be exploited in rational drug design. Science , issue p. 875
Abstract THIK-1 ( KCNK13 ) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K + channel implicated in microglial activation neuroinflammation, current target for the treatment of neurodegenerative disorders, example Alzheimer’s disease amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little known about structural functional properties THIK-1. Here we present 3.16-Å-resolution cryo-EM structure human that reveals several distinct...
Two-pore domain potassium (K(2P)) channels play a key role in setting the membrane potential of excitable cells. Despite their as putative targets for drugs and general anesthetics, little is known about structure drug binding site K(2P) channels. We describe A1899 potent highly selective blocker channel TASK-1. As acts an open-channel binds to residues forming wall central cavity, was used further our understanding pore. Using alanine mutagenesis screens, we have identified both pore loops,...
Highlights•Mechanogating of TREK-2 involves movement from the down to up conformation•Simulations sample a wide range mechanosensitive K2P channel structures•Changes in pressure profile and state-dependent lipid interactions play key role•Lipid block inner pore does not mediate stretch activationSummaryThe two-pore domain (K2P) K+ channels (TREK-1, TREK-2, TRAAK) are important for mechanical thermal nociception. However, mechanisms underlying their gating by membrane remain controversial....
The TREK subfamily of two-pore domain (K2P) K+ channels exhibit polymodal gating by a wide range physical and chemical stimuli. Crystal structures now exist for these in two main states referred to as the “up” “down” conformations. However, recent studies have resulted contradictory mutually exclusive conclusions about functional (i.e., conductive) status To address this problem, we used state-dependent TREK-2 inhibitor norfluoxetine that can only bind down state, thereby allowing us...
Research Article27 February 2017Open Access Transparent process Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia Niels Decher Corresponding Author [email protected] orcid.org/0000-0001-8892-1231 Institute of Physiology Pathophysiology, Vegetative Physiology, Philipps-University Marburg, Germany Search for more papers by this author Beatriz Ortiz-Bonnin Corinna Friedrich Department Cardiovascular Medicine, Genetics Heart Diseases (IfGH), University Hospital...
Abstract The two-pore domain potassium (K 2P ) channels TREK-1 and TREK-2 link neuronal excitability to a variety of stimuli including mechanical force, lipids, temperature phosphorylation. This regulation involves the C-terminus as polymodal stimulus sensor selectivity filter (SF) channel gate. Using crystallographic up- down-state structures template for full atomistic molecular dynamics (MD) simulations, we reveal that SF in undergoes inactivation via conformational changes, while...
Phosphatidylinositol polyphosphates (PIPs) are potent modulators of Kir channels. Previous studies have implicated basic residues in the C terminus Kir6.2 channels as interaction sites for PIPs. Here we examined role N and identified an arginine (Arg-54) a major determinant PIP2 modulation ATP sensitivity KATP Mutation Arg-54 to neutral glutamine (R54Q) and, particular, negatively charged glutamate (R54E) impaired inhibition, while mutation lysine (R54K) had no effect. These data suggest...
Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling electrical activity many different cell types and represent attractive therapeutic targets. However, identification highly selective small molecule drugs against these has been challenging due to high degree structural functional conservation that exists not only between K2P channels, but across whole K+ channel superfamily. To address issue selectivity, here we generate camelid...
Specific stimuli such as intracellular H+ and phosphoinositides (e.g., PIP2) gate inwardly rectifying potassium (Kir) channels by controlling the reversible transition between closed open states. This gating mechanism underlies many aspects of Kir channel physiology pathophysiology; however, its structural basis is not well understood. Here, we demonstrate that PIP2 use a conserved defined similar changes in transmembrane (TM) helices selectivity filter. Our data support model which motion...
The TREK subfamily of two-pore domain K+ (K2P) channels are inhibited by fluoxetine and its metabolite, norfluoxetine (NFx). Although not the principal targets this antidepressant, channel inhibition NFx has provided important insights into conformational changes associated with gating highlighted role selectivity filter in process. However, despite availability TREK-2 crystal structures bound, precise mechanisms underlying remain elusive. previously been proposed to be a state-dependent...
Abstract Sleep apnea is a common disorder that represents global public health burden. KCNK3 encodes TASK-1, K + channel implicated in the control of breathing, but its link with sleep remains poorly understood. Here we describe new developmental associated (developmental delay apnea, or DDSA) caused by rare de novo gain-of-function mutations . The cluster around ‘X-gate’, gating motif controls opening, and produce overactive channels no longer respond to inhibition G-protein-coupled...