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| Open AccessStructural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs
Glycine receptors (GlyRs) mediate motor control and pain perception. Here, Kumar et al. present structures of GlyR bound to Δ9 -tetrahydrocannabinol (THC) using cryo-electron microscopy, providing insight into the therapeutic effects of cannabinoids.
- Arvind Kumar
- , Kayla Kindig
- & Sudha Chakrapani
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Article
| Open AccessThe molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors
Bites by elapid snakes can result in life-threatening paralysis caused by α-neurotoxins blocking the neuromuscular nicotinic acetylcholine receptor. Here, the authors determine the cryo-EM structure of this receptor in complex with a short-chain α-neurotoxin.
- Mieke Nys
- , Eleftherios Zarkadas
- & Chris Ulens
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Article
| Open AccessCryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.
- Gamma Chi
- , Qiansheng Liang
- & Katharina L. Dürr
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Article
| Open AccessStructures of the T cell potassium channel Kv1.3 with immunoglobulin modulators
The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune responses. Here, the authors report structures of the Kv1.3 potassium channel with and without immunoglobulin modulators, shedding light on the mechanisms of Kv1.3 gating and modulation.
- Purushotham Selvakumar
- , Ana I. Fernández-Mariño
- & Joel R. Meyerson
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Article
| Open AccessStructures and gating mechanisms of human bestrophin anion channels
Bestrophin channels are critical for physiology of the eye. Here, authors report cryo-EM structures of human bestrophins in various states at up to 1.8 Å resolution, revealing paralog-specific features that underlie molecular mechanisms of permeation.
- Aaron P. Owji
- , Jiali Wang
- & Tingting Yang
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Article
| Open AccessStructural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277
KCNQ1 channels are active in heart, brain and gut. Functional loss causes epilepsy and sudden arrhythmic death. Here, authors describe a key activator drug binding site, explaining isoform and drug selectivity, and point the way for new drug design.
- Katrien Willegems
- , Jodene Eldstrom
- & David Fedida
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Article
| Open AccessMacrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
Mutations in the chloride channel CFTR that impair plasma membrane insertion and ion transport are the cause of cystic fibrosis. Here, the authors identify a macrocycle that stabilizes the interaction of mutant CFTR with the chaperone-like protein 14-3-3 and rescues its biological function.
- Loes M. Stevers
- , Madita Wolter
- & Christian Ottmann
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Article
| Open Access3D structure and in situ arrangements of CatSper channel in the sperm flagellum
Sperm motility and male fertility requires function of the CatSper calcium channels. Here, using cryo-electron tomography, authors visualize the native in-cell 3D structure and higher-order organization of the CatSper as long zigzag rows along the sperm tail.
- Yanhe Zhao
- , Huafeng Wang
- & Jean-Ju Chung
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Article
| Open AccessStructural Basis for pH-gating of the K+ channel TWIK1 at the selectivity filter
TWIK1 is a pH-gated K + channel highly expressed in brain and heart that contributes to cardiac rhythm and insulin release. Here, Turney et al. use cryo-EM and electrophysiology to show how TWIK1 gates closed in response to lowered pH through conformational changes centered at the selectivity filter.
- Toby S. Turney
- , Vivian Li
- & Stephen G. Brohawn
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Article
| Open AccessVanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis
Cryo-EM often yields multiple protein conformations within a single dataset. Using the thermal titration methods and cryo-EM, Do Hoon Kwon et al. elucidate the conformational trajectory of the TRPV1 with resiniferatoxin (RTx) bound.
- Do Hoon Kwon
- , Feng Zhang
- & Seok-Yong Lee
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Article
| Open AccessMolecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations
Ryanodine receptor 2 (RyR2) is a Ca2+ release channel essential for cardiac excitation-contraction coupling. Here, the authors use structural and functional analysis to reveal RyR2 gating mechanism and its alterations by pathogenic mutations.
- Takuya Kobayashi
- , Akihisa Tsutsumi
- & Haruo Ogawa
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Article
| Open AccessInhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC
TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is implicated in various diseases, but its pharmacology remains poorly understood. Here, the authors combine cryo-EM and electrophysiology to elucidate the mechanism of TMEM16A inhibition by the pore blocker 1PBC.
- Andy K. M. Lam
- , Sonja Rutz
- & Raimund Dutzler
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Article
| Open AccessStructural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
KATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic KATP in both the closed state and the pre-open state. These structures illuminate the mechanism of KATP channel regulation by the intracellular nucleotides.
- Mengmeng Wang
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessStructural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide
Loop diuretics including bumetanide inhibit Na+-K+-Cl−-cotransporters (NKCCs) and are used for the treatment of edema and hypertension. Here, Zhao et. al. report structures of NKCC1 with bumetanide bound, revealing its mechanism of action that would facilitate design of novel diuretics.
- Yongxiang Zhao
- , Kasturi Roy
- & Erhu Cao
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Article
| Open AccessN-type fast inactivation of a eukaryotic voltage-gated sodium channel
Voltage-gated sodium channels mediate electrical signaling. Here, authors report the cryo-EM structure of NaVEh from the marine plant Emiliania huxleyi, revealing an unexpected mechanism of N-type fast inactivation.
- Jiangtao Zhang
- , Yiqiang Shi
- & Daohua Jiang
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Article
| Open AccessStructural identification of vasodilator binding sites on the SUR2 subunit
SUR2-containing KATP channels are drug targets for certain vasodilators. Here, the authors determine high-resolution cryo-EM structures of SUR2 in complex with two vasodilators, P1075 and levcromakalim, uncovering the mechanisms of these drugs.
- Dian Ding
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessStructure of the Arabidopsis guard cell anion channel SLAC1 suggests activation mechanism by phosphorylation
The anion channel SLAC1 controls stomatal closure upon phosphoactivation. Here via structural analysis and electrophysiology, the authors propose an inhibition-release model where phosphorylation causes dissociation of a cytosolic plug from the SLAC1 transmembrane domains to induce conformational change in the pore-forming helices.
- Yawen Li
- , Yinan Ding
- & Linfeng Sun
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Article
| Open AccessStructural insights into TRPV2 activation by small molecules
A non-selective calcium channel transient receptor potential vanilloid 2 (TRPV2) is a potential drug target. Here, the authors employ cryo-electron microscopy, in silico docking, and electrophysiology to identify a binding site for an activator 2-aminoethoxydiphenyl borate (2-APB) in this channel.
- Ruth A. Pumroy
- , Anna D. Protopopova
- & Vera Y. Moiseenkova-Bell
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Article
| Open AccessPyridine nucleotide redox potential in coronary smooth muscle couples myocardial blood flow to cardiac metabolism
Physiological matching of blood flow to the demand for oxygen by the heart is required for sustained cardiac health, yet the underlying mechanisms are obscure. Here, the authors report a key role for acute modifications to the redox state of intracellular pyridine nucleotides in coronary smooth muscle and their impact on voltage-gated K + channels in metabolic vasodilation
- Marc M. Dwenger
- , Sean M. Raph
- & Matthew A. Nystoriak
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Article
| Open AccessStructure, gating, and pharmacology of human CaV3.3 channel
T-type calcium channels are implicated in many diseases. Here, multiple structures of CaV3.3 channel elucidate molecular mechanisms of T-type CaV channels activation at low voltage and interaction with different clinically used channel blockers.
- Lingli He
- , Zhuoya Yu
- & Yan Zhao
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Article
| Open AccessA distinct mechanism of C-type inactivation in the Kv-like KcsA mutant E71V
Constriction of the selectivity filter is assumed to be a hallmark of C-type inactivation in K+ channels. Using different high-resolution methods, this study shows a distinct C-type inactivation mechanism in a KcsA mutant that emulates Kv-channels.
- Ahmed Rohaim
- , Bram J. A. Vermeulen
- & Markus Weingarth
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Article
| Open AccessStructure-guided unlocking of NaX reveals a non-selective tetrodotoxin-sensitive cation channel
NaX is an atypical member of the voltage-gated sodium channel family that may contribute to Na+ homeostasis. Here, the authors describe the structural and functional attributes of the human NaX channel to reveal new insights into its physiology.
- Cameron L. Noland
- , Han Chow Chua
- & Jian Payandeh
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Article
| Open AccessStructural basis for activation and gating of IP3 receptors
IP3 receptors are intracellular calcium channels involved in numerous signaling pathways. Here, the authors present the cryo-EM structures of type-3 IP3 receptors in multiple gating conformations, including the active state revealing the molecular mechanism of the receptor activation.
- Emily A. Schmitz
- , Hirohide Takahashi
- & Erkan Karakas
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Article
| Open AccessIntrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2
A key question in mechanobiology is how mechanical forces are transmitted to PIEZO ion channels. Here, Verkest et al. identify an intracellular channel domain that is required for the activation of PIEZO2 by cytoskeleton-transmitted forces.
- Clement Verkest
- , Irina Schaefer
- & Stefan G. Lechner
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Article
| Open AccessStructural basis for modulation of human NaV1.3 by clinical drug and selective antagonist
NaV1.3 is involved in neuronal development, hormone secretion and pain perception. Here, the authors elucidate the molecular mechanism for modulation of NaV1.3 by a site-2 neurotoxin bulleyaconitine A and a subtype selective antagonist ICA121431.
- Xiaojing Li
- , Feng Xu
- & Daohua Jiang
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Article
| Open AccessiRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2
Cells that cannot cope with persistent endoplasmic reticulum stress will die. Here, the authors show that iRhom pseudoproteases regulate cell death by modulating the ability of BCL-2 to inhibit calcium flow through IP3R channels.
- Iqbal Dulloo
- , Peace Atakpa-Adaji
- & Matthew Freeman
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Article
| Open AccessTRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence
Mitochondrial Ca2+ homeostasis is reported to influence cellular senescence. Here the authors show that TRPC3 limits senescence by inhibiting IP3R-mediated Ca2+ release and ER mitochondria Ca2+ transfer and that the downregulation of TRPC3 in stromal cells affects SASP production and tumour progression.
- Valerio Farfariello
- , Dmitri V. Gordienko
- & Natalia Prevarskaya
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Article
| Open AccessStructural insights into the Venus flytrap mechanosensitive ion channel Flycatcher1
Flycatcher1 (FLYC1) is a candidate mechanosensitive channel involved in Venus flytrap touch-induced prey capture. Here, the authors report structural and functional details of FLYC1, with insights into gating conformational transitions.
- Sebastian Jojoa-Cruz
- , Kei Saotome
- & Andrew B. Ward
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Article
| Open AccessStructures of highly flexible intracellular domain of human α7 nicotinic acetylcholine receptor
The intracellular domain (ICD) of Cys-loop receptors mediates many of their functions, but no complete structure of a Cys-loop receptor ICD is available to date. Here, the authors combine NMR and ESR spectroscopy to determine the full-length ICD structures of the human α7 nicotinic acetylcholine receptor (α7nAChR).
- Vasyl Bondarenko
- , Marta M. Wells
- & Pei Tang
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Article
| Open AccessMechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor
AMPA glutamate receptors, mediate the majority of excitatory signaling in the brain. Here the authors show how the auxiliary subunit TARP-γ8 shapes gating kinetics, ion conductance and rectification properties of the heteromeric GluA1/2 AMPA receptor.
- Beatriz Herguedas
- , Bianka K. Kohegyi
- & Ingo H. Greger
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Article
| Open AccessMutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis
Antibiotic persisters are phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Here, the authors provide evidence that cytoplasmic acidification, amplified by a compromised respiratory complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.
- Bram Van den Bergh
- , Hannah Schramke
- & Matthias Heinemann
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Article
| Open AccessIon currents through Kir potassium channels are gated by anionic lipids
The Kir potassium channels are known to operate and gate without a major conformational change. Here, the authors identify the permeation gate of Kir channels as a steric plug within the conduction pathway, describing how tightly associated anionic lipids pushing into fenestrations in the pore walls engage with the plug to operate the gate.
- Ruitao Jin
- , Sitong He
- & Jacqueline M. Gulbis
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Article
| Open AccessIn vivo spatiotemporal control of voltage-gated ion channels by using photoactivatable peptidic toxins
Photoactivable toxins targeting ion channels have great potential to control cell activity. Here the authors report HwTxIV-Nvoc, a UV light-cleavable and photoactivatable peptide that targets voltage-gated sodium channels; they validate this in cells, brain slices and in vivo on mice neuromuscular junctions.
- Jérôme Montnach
- , Laila Ananda Blömer
- & Michel De Waard
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Article
| Open AccessSmall molecule modulation of the Drosophila Slo channel elucidated by cryo-EM
Slowpoke (Slo) channels are voltage-gated potassium channels that are activated by high intracellular Ca2+ concentrations, and they are targets for insecticides and antiparasitic drugs. Here, the authors present the cryo-EM structures of the Drosophila melanogaster Slo channel in the Ca2+-bound and Ca2+-free conformations, as well as in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside and discuss the mechanisms by which they affect the activity of Slo.
- Tobias Raisch
- , Andreas Brockmann
- & Stefan Raunser
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Article
| Open AccessProbing ion channel functional architecture and domain recombination compatibility by massively parallel domain insertion profiling
Here, the authors perform a large-scale, high-throughput biochemical assay to determine the compatibility of over 300,000 domain recombination variants of the inward rectifier K+ channel Kir2.1. They derive rules for designing domain insertion variants that fold and traffic to the cell surface and conclude that the insertion of domains at protein termini is evolutionary favoured.
- Willow Coyote-Maestas
- , David Nedrud
- & Daniel Schmidt
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Article
| Open AccessStructural basis for high selectivity of a rice silicon channel Lsi1
The rice Lsi1 aquaporin mediates uptake of silicic acid via the roots. Here the authors show the crystal structure of rice Lsi1 and characterize a unique five residue hydrophilic selectivity filter providing a structural basis for the highly selective activity of Lsi1 in Si uptake.
- Yasunori Saitoh
- , Namiki Mitani-Ueno
- & Michihiro Suga
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Article
| Open AccessIon-dependent structure, dynamics, and allosteric coupling in a non-selective cation channel
NaK is a bacterial non-selective cation channel. Here, the authors use solution NMR to show that selectivity filter (SF) in NaK is dynamic, with structural differences between the Na+ and K + -bound states. The conformation of the SF is communicated to the pore-lining helices similarly as in the K + -selective channels.
- Adam Lewis
- , Vilius Kurauskas
- & Katherine Henzler-Wildman
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Article
| Open AccessStructural determinants and regulation of spontaneous activity in GABAA receptors
GABAA receptors (GABAARs) cause inhibition in the brain by functioning as heteropentamers formed from multiple subunit types. Here, the authors demonstrate that receptors incorporating β3 subunits can spontaneously gate, which is modulated by protein kinases and neurosteroids to affect tonic inhibition.
- Craig A. Sexton
- , Reka Penzinger
- & Trevor G. Smart
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Article
| Open AccessAllosteric modulation of LRRC8 channels by targeting their cytoplasmic domains
Volume-regulated anion channels (VRACs) are heteromers of LRRC8 proteins, all containing the obligatory subunit LRRC8A. Here, the authors develop and characterize nanobodies that bind LRRC8A and allosterically modulate the function of homomeric LRRC8A and endogenous heteromeric channels, hinting at functional mechanisms present in VRACs.
- Dawid Deneka
- , Sonja Rutz
- & Raimund Dutzler
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Article
| Open AccessDeciphering ion transport and ATPase coupling in the intersubunit tunnel of KdpFABC
KdpFABC is a high-affinity bacterial K+ pump which combines the ion channel-like KdpA and the P-type ATPase KdpB. Here, the authors elucidate the mechanisms underlying transport and the coupling to ATP hydrolysis, and provide evidence that ions are transported via an intersubunit tunnel through KdpA and KdpB.
- Jakob M. Silberberg
- , Robin A. Corey
- & Inga Hänelt
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Article
| Open AccessElectrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection
Strategies to improve the function of damaged hearts with progenitor cells have stalled. Here, the authors show that gene transfer of a calcium-dependent potassium channel enhances the functional properties and ability of explant-derived cells to improve heart function after a heart attack.
- Patrick Vigneault
- , Sandrine Parent
- & Stanley Nattel
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Article
| Open AccessStructural basis for Ca2+ activation of the heteromeric PKD1L3/PKD2L1 channel
Hetero-oligomeric TRP-like channels such as PKD1L3/PKD2L1 play crucial roles in a range of physiological and pathophysiological processes. Here, the authors present the cryo-EM structures of a minimal functional murine PKD1L3/PKD2L1 complex in the absence and presence of calcium and further supported through structure-guided mutagenic studies, they discuss the mechanism of calcium-induced channel activation.
- Qiang Su
- , Mengying Chen
- & Yigong Shi
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Article
| Open AccessLsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles
Nicotinic acid adenine dinucleotide phosphate (NAADP) potent Ca2+ mobilizing second messenger which uniquely triggers Ca2+ release from acidic endolysosomal organelles. Here the authors identify Lsm12 as an NAADP receptor essential for NAADP-evoked Ca2+ release from lysosomes via NAADP binding on its Lsm domain.
- Jiyuan Zhang
- , Xin Guan
- & Jiusheng Yan
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Article
| Open AccessPrecise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin
Photocaged molecules have advantages in terms of temporal and spatial control compared to conventional pharmacological compounds. The authors present a synthetic saxitoxin derivative affixed to a photocleavable group for precise modulation of Na channels.
- Anna V. Elleman
- , Gabrielle Devienne
- & J. Du Bois
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Article
| Open AccessElectromechanical coupling mechanism for activation and inactivation of an HCN channel
Sea urchin hyperpolarization-activated cyclic nucleotide-gated (spHCN) ion channels channels are activated by membrane hyperpolarization instead of depolarization and undergo inactivation with hyperpolarization. Here authors apply transition metal ion FRET, patch-clamp fluorometry and Rosetta modeling to measure differences in the structural rearrangements between activation and inactivation of spHCN channels.
- Gucan Dai
- , Teresa K. Aman
- & William N. Zagotta
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Article
| Open AccessExtracellular cap domain is an essential component of the TRPV1 gating mechanism
Structural and functional characterization of the full-length TRPV1 channel from the thirteen-lined ground squirrel reveal the architecture of the extracellular cap domain and the intracellular C-terminus, and suggest a role of the cap domain in TRPV1 conductance and ion selectivity.
- Kirill D. Nadezhdin
- , Arthur Neuberger
- & Alexander I. Sobolevsky
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Article
| Open AccessLipid regulation of hERG1 channel function
The lipid regulation of mammalian ion channel function has emerged as a fundamental mechanism in the control of electrical signalling and transport specificity. Here, the authors combine molecular dynamics simulations, mutagenesis, and electrophysiology to provide mechanistic insights into how lipophilic molecules alter gating kinetics and K+ currents of hERG1.
- Williams E. Miranda
- , Jiqing Guo
- & Sergei Yu. Noskov
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Article
| Open AccessArachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation
ORAI3 is part of pore forming calcium channels involved in T cell activation. Here the authors show that there is increased expression of ORAI3 in T cells from patients with rheumatoid arthritis and that the transcription factor IKAROS negatively regulates the ORAI3 promoter, indicating a regulatory loop that can control auto-reactivity of T cells in these patients.
- Zhongde Ye
- , Yi Shen
- & Jörg J. Goronzy
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Article
| Open AccessLigand-directed two-step labeling to quantify neuronal glutamate receptor trafficking
The analysis of AMPA-type glutamate receptor (AMPAR) trafficking is essential for understanding molecular mechanisms of learning and memory, but the analytical tools are currently limited. Here, the authors report a method that combines affinity-based receptor labeling and bioorthogonal click chemistry to quantify AMPAR distribution and trafficking under physiological conditions.
- Kento Ojima
- , Kazuki Shiraiwa
- & Shigeki Kiyonaka