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| Open AccessThree-dimensional liquid metal-based neuro-interfaces for human hippocampal organoids
Providing a suitable multi-electrode array (MEA) for free-floating neural organoids is a great challenge. Here, authors present a mesh soft stretchable MEA for recording neural signals in human hippocampal organoids derived from induced pluripotent stem cells.
- Yan Wu
- , Jinhao Cheng
- & Xingyu Jiang
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Article
| Open AccessT-DOpE probes reveal sensitivity of hippocampal oscillations to cannabinoids in behaving mice
Neural activity is regulated by synapse-neuromodulator interactions, necessitating optoelectro-pharmacological investigations. Here, authors implement their multi-modal probe to show focal infusion of synthetic cannabinoid disrupts CA1 oscillations.
- Jongwoon Kim
- , Hengji Huang
- & Xiaoting Jia
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Article
| Open AccessA high affinity switch for cAMP in the HCN pacemaker channels
Cyclic AMP modulation of HCN channels underlies beta adrenergic stimulation of heart rate. Here, authors describe an intramolecular mechanism that controls cAMP affinity of the cyclic nucleotide binding domain of these channels.
- Alessandro Porro
- , Andrea Saponaro
- & Anna Moroni
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Article
| Open AccessShape-changing electrode array for minimally invasive large-scale intracranial brain activity mapping
The invasiveness of extensive craniotomy hinders large-scale cortex mapping. Here, the authors developed a flexible, shape-changing electrode array which enables minimally invasive implantation and achieves high spatiotemporal resolution brain mapping.
- Shiyuan Wei
- , Anqi Jiang
- & Xiaojie Duan
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Article
| Open AccessPIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome
PIEZO1 is a mechanosensitive ion channel. Here, authors identify PIEZO1 human mutations in Prune Belly Syndrome. At a single molecule level these mutations exhibit loss-of-function characteristics.
- Nathalia G. Amado
- , Elena D. Nosyreva
- & Ruhma Syeda
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Article
| Open AccessSelective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine
L-type voltage-gated calcium channels are involved in multiple physiological functions. Here the authors identify calciseptine, a toxin purified from black mamba venom, as a selective inhibitor of Cav1.2 L-type Ca2+ channels.
- Pietro Mesirca
- , Jean Chemin
- & Joël Nargeot
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Article
| Open AccessElucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors
Insects rely on olfaction for behavior control. Recent structural studies of receptors provide insight into ligand binding. Here, the authors identify dynamic binding mechanism to Orco, explaining its high selectivity with insights in compound screening.
- Jody Pacalon
- , Guillaume Audic
- & Jérémie Topin
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Article
| Open AccessCryo-EM structures of the plant anion channel SLAC1 from Arabidopsis thaliana suggest a combined activation model
Phosphorylation-mediated activation of SLAC1 anion channel is crucial in plant responses for abiotic stresses including drought. Here, authors determine the open and closed structures of SLAC1, revealing how phosphorylation can activate SLAC1.
- Yeongmok Lee
- , Hyeon Seong Jeong
- & Sangho Lee
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Article
| Open AccessProgesterone activation of β1-containing BK channels involves two binding sites
Progesterone is used in recovery of cerebral ischemia however the mechanism of action is unknown. Authors report here that micromolar progesterone activates mouse cerebrovascular myocyte BK channels, involving two steroid binding sites.
- Kelsey C. North
- , Andrew A. Shaw
- & Alex M. Dopico
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Article
| Open AccessAsymmetric gating of a human hetero-pentameric glycine receptor
Despite essential roles in adult nervous systems, how heteromeric Cys-loop receptors work is unclear in the absence of an open state structure. Here, the authors report closed/open state structures and functional experiments, detailing an asymmetric gating mechanism driven by differing contributions from each subunit type.
- Xiaofen Liu
- & Weiwei Wang
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Article
| Open AccessA mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels
Here, authors have identified two pairs of large hydrophobic residues in the channel S6 segments that form the inactivation gate of eukaryotic Na+ channels.
- Yichen Liu
- , Carlos A. Z. Bassetto Jr
- & Francisco Bezanilla
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Article
| Open AccessIdentification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase
TMEM16F is a Ca2+ activated ion channel and lipid scramblase involved in cell fusion. Here authors determine cryo-EM structures of TMEM16F with or without bound blockers, such as the FDA-approved drug niclosamide.
- Shengjie Feng
- , Cristina Puchades
- & Lily Yeh Jan
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Article
| Open AccessCysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR)
Oxidation of ryanodine receptor calcium channels play a critical role in the onset of many cardiac diseases. Here, authors identify specific amino acids that cause ryanodine receptor malfunction during oxidative stress.
- Roman Nikolaienko
- , Elisa Bovo
- & Aleksey V. Zima
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Article
| Open AccessStructure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red
The voltage-dependent CALHM1 channel is critical in neuromodulation and gustatory signaling. The authors present cryo-EM structures of human CALHM1 in apo- and blocked-states. They explore effects of lipid binding on channel structure and activity.
- Johanna L. Syrjänen
- , Max Epstein
- & Hiro Furukawa
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Article
| Open AccessIntracranial electrophysiological and structural basis of BOLD functional connectivity in human brain white matter
Whether connectivity in white matter detected by functional MRI relates to underlying electrophysiological synchronization is unclear. Here, the authors show that blood-oxygenation-level-dependent (BOLD) functional connectivity and intracranial stereotactic-electroencephalography (SEEG) connectivity are correlated across a wide range of frequency bands.
- Yali Huang
- , Peng-Hu Wei
- & Guoguang Zhao
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Article
| Open AccessAnt venoms contain vertebrate-selective pain-causing sodium channel toxins
Stings of certain ant species can cause intense, long-lasting nociception. Here, authors show that the major contributors of these symptoms are vertebrate-selective defensive venom peptides which modulate the activity of voltage-gated sodium channels.
- Samuel D. Robinson
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessVesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry
In glutamatergic neurons, synaptic vesicles contain glutamate, but not aspartate. Here, the authors show that vesicular glutamate transporters are H+/anion exchangers that attain high selectivity for glutamate via variable transport coupling.
- Bettina Kolen
- , Bart Borghans
- & Christoph Fahlke
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Article
| Open AccessTwo single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1
TRPV1 is a noxious heat sensor. Here, authors showed that tailed amphibians express TRPV1 with a reduced heat-activation threshold by substitution of two amino acids in the N-terminal region to contribute to cool-habitat selection.
- Shogo Hori
- , Michihiro Tateyama
- & Osamu Saitoh
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Article
| Open AccessChemogenetic attenuation of cortical seizures in nonhuman primates
Pharmacological and surgical treatments of epilepsy can have unsatisfactory outcomes, so a more targeted and on-demand approach is desirable. Here, the authors demonstrate the usage of inhibitory chemogenetics in male nonhuman primates to attenuate the magnitude and spread of cortical seizures and subsequent body convulsions.
- Naohisa Miyakawa
- , Yuji Nagai
- & Takafumi Minamimoto
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Article
| Open AccessA gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation
TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
- Qiaochu Wang
- , Zengge Wang
- & Wei Li
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| Open AccessStructure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
TRPV1 as a drug target suffers from side effects of hypothermia. Here, authors engineer a peptide, sRhTx, as a positive allosteric modulator of TRPV1 channel. It potentiates the activity of TRPV1 to reversibly ablate pain-sensing nerve terminals for long-lasting analgesia without changing mice body temperature.
- Heng Zhang
- , Jia-Jia Lin
- & Fan Yang
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Article
| Open AccessVertebrate OTOP1 is also an alkali-activated channel
pH sensation is critical for survival of vertebrates. Here, authors found six vertebrate OTOP1 channels that were highly conserved and directly activated by extracellular alkali. Key mutations of OTOP1 reduced alkali affinity without affecting acid activation.
- Lifeng Tian
- , Hao Zhang
- & Ren Lai
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Article
| Open AccessMultimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex
Neuronal organoids derived from human induced pluripotent stem cells can be transplanted and integrated into the rodent cortex for the study of brain development and function. Here the authors demonstrate use of transparent graphene microelectrodes and two photon imaging for longitudinal, multimodal monitoring of functional connectivity between human iPSC derived neuronal organoids and the mouse cortex.
- Madison N. Wilson
- , Martin Thunemann
- & Duygu Kuzum
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Article
| Open AccessActivating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility
Antibiotic resistance through multidrug efflux is a major hurdle in antibiotic development. Here, authors experimentally demonstrate that EmrE, a small multidrug resistance efflux pump from E. coli, can confer resistance or susceptibility depending on the small molecule substrate.
- Peyton J. Spreacker
- , Nathan E. Thomas
- & Katherine A. Henzler-Wildman
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Article
| Open AccessGating and ion selectivity of Channelrhodopsins are critical for photo-activated orientation of Chlamydomonas as shown by in vivo point mutation
Channelrhodopsin photoreceptors are responsible for phototaxis in C. reinhardtii. Here, authors introduce point mutations in the channel which modify photocycle kinetics and ion selectivity, resulting in a deeper understanding of phototaxis in low light conditions.
- Olga Baidukova
- , Johannes Oppermann
- & Peter Hegemann
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Article
| Open AccessAn allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening
Ca2+ activated BK channels are important for neural and muscle function. Here authors use a compound, BC5, to show that the interface between the cytosolic and voltage sensing domains is a major allosteric pathway for Ca2+ binding to open the channel.
- Guohui Zhang
- , Xianjin Xu
- & Jianmin Cui
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Article
| Open AccessFunctional architecture of executive control and associated event-related potentials in macaques
The authors examine the cortical microcircuitry relating to executive control in macaques. They describe three classes of neurons that signal response conflict, event timing, and maintenance of task goals, as well as their relations with event-related potentials that are associated with response inhibition.
- Amirsaman Sajad
- , Steven P. Errington
- & Jeffrey D. Schall
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Article
| Open AccessNeural probe system for behavioral neuropharmacology by bi-directional wireless drug delivery and electrophysiology in socially interacting mice
Technologies for monitoring electrophysiological effects of drugs in behaving animals have limitations. Here the authors report a wireless neural probe system with drug delivery capability for real-time monitoring of drug effects.
- Yousang Yoon
- , Hyogeun Shin
- & Il-Joo Cho
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Article
| Open AccessSegregated cation flux by TPC2 biases Ca2+ signaling through lysosomes
TPC2 is a lysosomal ion channel permeable to both calcium and sodium ions. Here, the authors show that TPC2 can selectively increase its calcium permeability when simultaneously challenged by both its natural activators- NAADP and PI(3,5)P2.
- Yu Yuan
- , Dawid Jaślan
- & Sandip Patel
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Article
| Open AccessFunctional neuronal circuitry and oscillatory dynamics in human brain organoids
Brain organoids replicate cellular organization found in the developing human brain. Here, the authors utilize microelectronics to map activity in brain organoids and assemble functional circuits that mirror complexity found in brain networks in vivo.
- Tal Sharf
- , Tjitse van der Molen
- & Kenneth S. Kosik
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Article
| Open AccessMapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers
Quantitative characterization of kinase conformational dynamics remains challenging. Here, the authors show that protein nanopore tweezers allow analyzing the conformational energy landscape and ligand binding of the Abl kinase domain.
- Fanjun Li
- , Monifa A. Fahie
- & Min Chen
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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 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 AccessSpelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training
The authors record neural firing rates in a patient with ALS in completely locked-in state and show that the patient can modulate neural firing rates based on auditory feedback to select letters to form words and phrases to communicate his needs and experiences.
- Ujwal Chaudhary
- , Ioannis Vlachos
- & Niels Birbaumer
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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 AccessSonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels
Ultrasound can be used to non-invasively control neuronal functions. Here the authors report the use of human Transient receptor potential ankyrin 1 (hsTRPA1) to achieve ultrasound sensitivity in mammalian cells, and show that it can be used to manipulate neurons in the mammalian brain.
- Marc Duque
- , Corinne A. Lee-Kubli
- & Sreekanth H. Chalasani
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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 AccessGasdermin D pores are dynamically regulated by local phosphoinositide circuitry
During pyroptosis, gasdermin D (GSDMD) forms plasma membrane pores that initiate cell lysis. Here, the authors develop optogenetically activatable human GSDMD to assess GSDMD pore behavior and show that they are dynamic and can close, which can be a pyroptosis regulatory mechanism.
- Ana Beatriz Santa Cruz Garcia
- , Kevin P. Schnur
- & Gary C. H. Mo
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Article
| Open AccessSelf-assembled multifunctional neural probes for precise integration of optogenetics and electrophysiology
The authors present a viral vector-delivery optrode system to integrate optogenetics and electrophysiology. The flexible microelectrode filaments and fiber optics self-assemble in a nanoliter-scale, viral vector-delivery polymer carrier for localized delivery and expression of opsin genes at microelectrode-tissue interfaces.
- Liang Zou
- , Huihui Tian
- & Ying Fang
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Article
| Open AccessEnabling comprehensive optogenetic studies of mouse hearts by simultaneous opto-electrical panoramic mapping and stimulation
Current cardiac mapping systems provide either electrical or optical readouts. Here the authors report a panoramic opto-electrical measurement and stimulation (POEMS) system which embraces the entire ventricular surface of mouse hearts, allowing flexible combinations of optical and electrical recording and stimulation modalities.
- Michael Rieger
- , Christian Dellenbach
- & Stephan Rohr
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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 AccessElectrode pooling can boost the yield of extracellular recordings with switchable silicon probes
Silicon probes for electrical recording from neurons usually have fewer wires than recording channels available to carry signals off the probe, which restricts the number of channels that can be recorded simultaneously. The authors propose to pool electrodes, using a single wire to serve many channels through a set of controllable switches.
- Kyu Hyun Lee
- , Yu-Li Ni
- & Markus Meister
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Article
| Open AccessDefining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase
The nature of the mitochondrial permeability transition pore (PTP) is still under debate. Here, through genetically modified F-ATP synthase, the authors show that PTP formation can be mediated by F-ATP synthase or by adenine nucleotide translocator, suggesting the existence of distinct but related permeability pathways.
- Andrea Carrer
- , Ludovica Tommasin
- & Paolo Bernardi
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Article
| Open AccessDeacetylation as a receptor-regulated direct activation switch for pannexin channels
Pannexin 1 (PANX1) is a membrane channel mediating release of signaling molecules to the extracellular space. PANX1 can be activated by GPCRs. Here, the authors elucidate a non-canonical channel activation pathway by α1-adrenergic receptor that involves HDAC6- mediated lysine deacetylation of PANX1.
- Yu-Hsin Chiu
- , Christopher B. Medina
- & Douglas A. Bayliss
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Article
| Open AccessMolecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases
TMEM16 lipid scramblases transport lipids and also operate as ion channels with highly variable ion selectivities and various physiological functions. Using computational electrophysiology simulations, the authors identify the main ion-conductive state of TMEM16 lipid scramblases and find that lipid headgroups modulate ion permeability and regulate ion selectivity of TMEM16 proteolipidic pores.
- Andrei Y. Kostritskii
- & Jan-Philipp Machtens
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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 AccessIncreased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.
- Julie C. Lauterborn
- , Pietro Scaduto
- & Agenor Limon
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Perspective
| Open AccessToward integrative approaches to study the causal role of neural oscillations via transcranial electrical stimulation
Transcranial electrical stimulation techniques may enable exploration of the role of neural oscillations in the brain. Here, the authors provide a perspective on its potential across systems, species, theoretical and experimental scales.
- Valeriia Beliaeva
- , Iurii Savvateev
- & Rafael Polania
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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