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| Open AccessReverse optogenetics of G protein signaling by zebrafish non-visual opsin Opn7b for synchronization of neuronal networks
Microbial rhodopsins can be used to control action potentials, while animal opsins can be used to control intracellular signaling pathways. The authors identify Opn7b as constitutively active Gi/o coupled receptor that can be deactivated by light and used to modulate neuronal activity.
- Raziye Karapinar
- , Jan Claudius Schwitalla
- & Stefan Herlitze
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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 AccessConformational rearrangement of the NMDA receptor amino-terminal domain during activation and allosteric modulation
N-Methyl-D-aspartate receptors (NMDARs) activation involves closure of the GluN1 and GluN2 subunit ligand binding domains, which is regulated allosterically by the amino-terminal domain (ATD). Here, smFRET, used to monitor conformational rearrangements of the NMDAR ATD, reveals that glutamate binding to GluN2 subunits elicits two identical, sequential steps of ATD dimer separation that are regulated by protons.
- Vojtech Vyklicky
- , Cherise Stanley
- & Ehud Y. Isacoff
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Article
| Open AccessNeuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension
TRPV4 dominant mutations cause neuropathy. Here, the authors show that TRPV4 binds and interacts with RhoA, modulating the actin cytoskeleton. Neuropathy-causing mutations of TRPV4 disrupt this complex, leading to RhoA activation and impairment of neurite extension in cultured cells and flies.
- Brett A. McCray
- , Erika Diehl
- & Charlotte J. Sumner
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Article
| Open AccessStructure of voltage-modulated sodium-selective NALCN-FAM155A channel complex
The NALCN channel mediates sodium leak currents, which in turn adjusts resting membrane potential and neuronal excitability. Here the authors describe a cryo-EM structure of mammalian NALCN-FAM155A channel complex, showing how selectivity filter contributes to sodium permeation and calcium block and how the voltage sensors contribute to current modulation.
- Yunlu Kang
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessStructure of the human sodium leak channel NALCN in complex with FAM155A
NALCN, a sodium leak channel, plays a key role in regulating the resting membrane potential and controlling neuronal excitability. Here the authors report a cryo-EM structure of human NALCN in complex with FAM155A, that with complementary functional analyses provide insights on its ion selectivity, voltage sensing and specific interactions with auxiliary subunits.
- Jiongfang Xie
- , Meng Ke
- & Zhen Yan
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Article
| Open AccessThe desensitization pathway of GABAA receptors, one subunit at a time
GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key contribution of the γ2 subunit during desensitization.
- Marc Gielen
- , Nathalie Barilone
- & Pierre-Jean Corringer
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Article
| Open AccessIntellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex
The sodium-leak channel NALCN controls the resting membrane potentials of neurons. Here, the authors identified two subunits of NALCN, UNC80 and UNC79. Domains in UNC80, which are mutated in individuals with intellectual disability, interact to achieve the dendritic localization of NALCN complex.
- Jinhong Wie
- , Apoorva Bharthur
- & Dejian Ren
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Article
| Open AccessTRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+
Mutations in the TRPV4 channel cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here the authors reveal that TRPV4 activation causes dose-dependent, CaMKII-mediated neuronal dysfunction and axonal degeneration via disruption of mitochondrial axonal transport.
- Brian M. Woolums
- , Brett A. McCray
- & Thomas E. Lloyd
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Article
| Open AccessSpider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels
Loss of function of Nav1.7 leads to congenital insensitivity to pain in humans. Here the authors found that activation of Nav1.9 can restore nociception in Nav1.7 knockout mice, revealed by a venom-derived peptide as a probe.
- Xi Zhou
- , Tingbin Ma
- & Zhonghua Liu
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Article
| Open AccessAn axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons
The precise subcellular location of ion channels is a key determinant of their functions. Here, subcellular patch-clamp recordings demonstrate that an axon-specific expression of HCN channels facilitates the initiation and propagation of action potentials in parvalbumin-expressing basket cells.
- Fabian C. Roth
- & Hua Hu
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Article
| Open AccessActivity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive flexibility
K + channels function in macromolecular complexes with accessory subunits to regulate neuronal function. Here, the authors describe Pin1-mediated regulation of the Kv4.2 complex, which impacts reversal learning in mice, providing potential treatment for disorders characterized by cognitive inflexibility.
- Jia–Hua Hu
- , Cole Malloy
- & Dax A. Hoffman
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Article
| Open AccessGating mechanism of hyperpolarization-activated HCN pacemaker channels
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for rhythmic activity in the heart and brain. Here authors reverse the voltage dependence of HCN channels by mutating only two residues located at the interface between the voltage sensor and the pore domain.
- Rosamary Ramentol
- , Marta E. Perez
- & H. Peter Larsson
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Article
| Open AccessLupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory
Systemic lupus erythematosus (SLE) is an autoimmune disorder which can have neurological manifestations, including autoantibody targeting of the NMDA receptor. In this study, the authors GluN2A subunit is a target of SLE autoantibodies, using sample derived from patient.
- Kelvin Chan
- , Jacquelyn Nestor
- & Lonnie P. Wollmuth
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Article
| Open AccessEnhancing neuronal chloride extrusion rescues α2/α3 GABAA-mediated analgesia in neuropathic pain
Disinhibition in the dorsal horn of the spinal cord may contribute to chronic pain. Here the authors show that, despite a paradoxical increase in α2/α3 subunits of the GABAA receptor in a neuropathic pain model, inhibition eventually fails due to KCC2 hypofunction.
- Louis-Etienne Lorenzo
- , Antoine G. Godin
- & Yves De Koninck
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Article
| Open AccessPositive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility
NMDA receptors undergo constant cycling into and out of the postsynaptic density. Here authors show that NMDAR's GluN1 subunit is required to maintain NMDARs at dendritic spine synapses by direct extracellular interaction with the receptor tyrosine kinase EphB2.
- Halley R. Washburn
- , Nan L. Xia
- & Matthew B. Dalva
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Article
| Open AccessDisruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis
Acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1). Here authors show that auto-inhibition of ASICa prevents RIPK1 recruitment and demonstrate that targeting the auto-inhibition has therapeutic potential to prevent acidotoxicity.
- Jing-Jing Wang
- , Fan Liu
- & Tian-Le Xu
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Article
| Open AccessStructural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors
Selectively inhibiting N-Methyl-D-aspartate receptors (NMDARs) containing the GluN2C/2D subunits has been challenging. Here, using electrophysiology and X-ray crystallography, authors show that compounds UBP791 and UBP1700 show over 40- and 50-fold selectivity for GluN2C/2D compared to GluN2A.
- Jue Xiang Wang
- , Mark W. Irvine
- & Hiro Furukawa
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Article
| Open AccessAn efficient analytical reduction of detailed nonlinear neuron models
Realistic simulations of neurons and neural networks are key for understanding neural computations. Here the authors describe Neuron_Reduce, an analytic approach to simplify neurons receiving thousands of synapses and accelerate their simulations by 40–250 folds, while preserving voltage dynamics and dendritic computations.
- Oren Amsalem
- , Guy Eyal
- & Idan Segev
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Article
| Open AccessAMPA receptors in the synapse turnover by monomer diffusion
The mechanisms regulating the turnover of the AMPARs in the synapse, which is critically important to sustain basic synaptic activity, remains unclear. In this study, authors used single-molecule imaging techniques to demonstrate that AMPAR tetramers are not stable entities and readily fall apart to dimers and monomers that could reform to tetramers at the synapse, and that rapidly diffusing monomers in the plasma membrane are primarily responsible for the AMPAR turnover in the synapse.
- Jyoji Morise
- , Kenichi G. N. Suzuki
- & Shogo Oka
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Article
| Open AccessCav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
Voltage-gated Ca2+ channels are thought to contribute to neurodegeneration of dopaminergic neurons. Here the authors find that the R-type channel Cav2.3 in substantia nigra dopaminergic neurons may contribute to neurodegeneration in a model of Parkinson’s disease, in contrast to the neuroprotective action of the neuronal Ca2+ sensor NCS-1.
- Julia Benkert
- , Simon Hess
- & Birgit Liss
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Article
| Open AccessPlasticity in striatal dopamine release is governed by release-independent depression and the dopamine transporter
Dopamine release in the striatum has important roles in action selection and in disorders such as Parkinson’s disease. The authors here show that short-term plasticity of dopamine release is strongly determined by axonal activation and dopamine transporters.
- Mark D. Condon
- , Nicola J. Platt
- & Stephanie J. Cragg
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Article
| Open Accessp97 regulates GluA1 homomeric AMPA receptor formation and plasma membrane expression
AMPA receptors mediate excitatory synaptic transmission and are involved in synaptic plasticity. The authors show that p97 interacts with the GluA1 subunit of AMPA receptors, promotes the formation of GluA1 homomeric AMPA receptors, and regulates AMPA receptor trafficking during synaptic plasticity.
- Yuan Ge
- , Meng Tian
- & Yu Tian Wang
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Article
| Open AccessSp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1
The adaptor protein p11 and K+ channel TASK1 have overlapping distributions in the CNS. Here, the authors demonstrate that the transcription factor Sp1 regulates p11 levels, which in turn affects intrinsic membrane properties and can contribute to degeneration of motor neurons in disease and injury models.
- Victoria García-Morales
- , Guillermo Rodríguez-Bey
- & Bernardo Moreno-López
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Article
| Open AccessAMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”
- Vincenzo Salpietro
- , Christine L. Dixon
- & Henry Houlden
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Article
| Open AccessMolecular basis for heat desensitization of TRPV1 ion channels
The heat-sensitive ion channel TRPV1 is essential to temperature sensing in mammals and other animals. Here the authors find that the platypus form of TRPV1 does not desensitize, identify the mechanism underlying this property, and show that knock-in of this form of the receptor in mice leads to deficits in heat sensitivity.
- Lei Luo
- , Yunfei Wang
- & Ren Lai
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Article
| Open AccessMutation of a single residue promotes gating of vertebrate and invertebrate two-pore domain potassium channels
Mutations that modulate the activity of ion channels are essential tools to understand the biophysical determinants that control their gating. Here authors reveal the role played by a single residue in the second transmembrane domain of vertebrate and invertebrate two-pore domain potassium channels.
- Ismail Ben Soussia
- , Sonia El Mouridi
- & Thomas Boulin
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Article
| Open AccessStructural elements of a pH-sensitive inhibitor binding site in NMDA receptors
Context-dependent inhibition of NMDA receptors has important therapeutic implications for treatment of neurological diseases. Here, the authors use structural biology and biophysics to describe the basis for pH-dependent inhibition for a class of allosteric NMDAR inhibitors, called the 93-series.
- Michael C. Regan
- , Zongjian Zhu
- & Hiro Furukawa
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Article
| Open AccessMembrane water for probing neuronal membrane potentials and ionic fluxes at the single cell level
Non-invasive spatiotemporal probing of electric potentials in living neurons without chemical or genetic modification provides a major advancement to neuroscience. Here, the authors demonstrate the use of membrane water as a probe for neuronal membrane potentials and ionic flux.
- M. E. P. Didier
- , O. B. Tarun
- & S. Roke
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Article
| Open AccessSignal peptide represses GluK1 surface and synaptic trafficking through binding to amino-terminal domain
The two kainate receptors GluK1 and GluK2 show different surface expression and synaptic trafficking. Here authors engineer chimeric GluK1-GluK2 receptors and decipher a role how the signal peptide of GluK1 behaves as a ligand of GluK1 and modifies surface expression and trafficking.
- Gui-Fang Duan
- , Yaxin Ye
- & Nengyin Sheng
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Article
| Open AccessSlc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations
Kv1.2 is a voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. Here authors use electrophysiology and find that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2.
- Victoria A. Baronas
- , Runying Y. Yang
- & Harley T. Kurata
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Article
| Open AccessA mechanoelectrical mechanism for detection of sound envelopes in the hearing organ
The sound envelope is important for speech perception. Here, the authors look at mechanisms by which the sound envelope is encoded, finding that it arises from distortion produced by mechanoelectrical transduction channels. Surprisingly, the envelope is not present in basilar membrane vibrations.
- Alfred L. Nuttall
- , Anthony J. Ricci
- & Anders Fridberger
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Article
| Open AccessHigh-efficiency optogenetic silencing with soma-targeted anion-conducting channelrhodopsins
Current optogenetic inhibition methods like light-controlled ion pumps require high-intensity light and disrupt physiological ion gradients. Here, the authors somatically target the anion-conducting opsin GtACR to eliminate spiking in distal axons and improve photocurrents, thus enhancing its utility.
- Mathias Mahn
- , Lihi Gibor
- & Ofer Yizhar
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Article
| Open AccessIdentification of small-molecule ion channel modulators in C. elegans channelopathy models
Mutations in the voltage-gated K+ channel human ether-a-go-go-related gene (hERG) lead to Long-QT syndrome, causing life-threatening cardiac arrhythmia. Here the authors use C. elegans as a platform to run a channelopathy drug screen, identifying drugs to target hERG mutants.
- Qiang Jiang
- , Kai Li
- & Shi-Qing Cai
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Article
| Open AccessA conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca2+ permeability
Little is known about the impact of de novo and inherited missense mutations in the NMDA receptor M4 transmembrane helices. In this study, the authors use functional and computational approaches to demonstrate how mutations to conserved glycine sites within this region cause structural rearrangement, altered receptor deactivation and calcium permeability.
- Johansen B. Amin
- , Xiaoling Leng
- & Lonnie P. Wollmuth
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Article
| Open AccessDendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABAA receptors
Somatostatin+ (SOM+ ) GABAergic interneurons are known to fine-tune synaptic plasticity as they inhibit dendritic spikes and burst firing. Here, the authors show that both SOM+ and NOS+ interneurons preferentially recruit nonlinear outward-rectifying GABA(A)R with alpha5 subunit, and that this inhibition with slow gating kinetics matches voltage and time-dependent activation of synaptic NMDARs, thereby controlling the generation of dendritic NMDA spikes.
- Jan M. Schulz
- , Frederic Knoflach
- & Josef Bischofberger
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Article
| Open AccessDevelopmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
The inhibitory synaptic protein collybistin (CB) and GABAAR-α subunits are thought to interact, but strength and specificity are unclear. Here the authors study the CB–α2 interaction and show that a mouse mutated in the CB-binding region of α2 displays a loss of specific synapses and seizure.
- Rochelle M. Hines
- , Hans Michael Maric
- & Stephen J. Moss
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Article
| Open AccessDirect neurotransmitter activation of voltage-gated potassium channels
M-current is conveyed by voltage-sensitive KCNQ channels, which are enriched in GABAergic neurons and are activated by anticonvulsants such as retigabine. Here the authors show that GABA directly activates KCNQ3, at the residue required for its anticonvulsant activity.
- Rían W. Manville
- , Maria Papanikolaou
- & Geoffrey W. Abbott
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Article
| Open AccessImproved calcium sensor GCaMP-X overcomes the calcium channel perturbations induced by the calmodulin in GCaMP
The popular genetically-encoded Ca2+ indicator, GCaMP, has several side-effects. Here the authors show that GCaMP containing CaM interferes with gating and signaling of L-type calcium channels, which disrupts Ca2+ dynamics and gene expression, and develop GCaMP-X to overcome these limitations.
- Yaxiong Yang
- , Nan Liu
- & Xiaodong Liu
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Article
| Open AccessThe ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel
Two subclasses of ligand-gated ion channels (ASIC3 and P2X3) are both present at sensory neurons and might be therefore subject to receptor crosstalk. Here authors use electrophysiology, biochemistry and co-immunoprecipitation to show that the two ion channels interact and affect P2X3 currents.
- Gabriele Stephan
- , Lumei Huang
- & Peter Illes
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Article
| Open AccessA lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel
Piezo1 is a large trimeric ion channel activated by mechanical stimulus. Here the authors identify chemical activators of Piezo1 that utilize a lever-like mechanotransduction pathway for long-range allosteric gating.
- Yanfeng Wang
- , Shaopeng Chi
- & Bailong Xiao
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Article
| Open AccessVoltage gating of mechanosensitive PIEZO channels
PIEZO proteins form mechanosensitive ion channels. Here the authors present electrophysiological measurements that show that PIEZO channels are also modulated by voltage and can switch to a purely voltage gated mode, which is an evolutionary conserved property of this channel family.
- Mirko Moroni
- , M. Rocio Servin-Vences
- & Gary R. Lewin
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Article
| Open AccessDisease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties
N-methyl-d-aspartate-receptors (NMDARs) are glutamate receptors critical for synaptic transmission, plasticity, and cognition. Here, the authors look at four neurodevelopmental disease-related mutations of NMDAR, gaining insight into binding of Mg2+ and mechanism of memantine, an NMDAR antagonist.
- Laura Fedele
- , Joseph Newcombe
- & Trevor G. Smart
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Article
| Open AccessSensory TRP channels contribute differentially to skin inflammation and persistent itch
Allergic contact dermatitis is associated both with persistent itch and inflammation, but it is not known if these are mediated by shared signaling pathways. The authors show that persistent itch requires both TRPA1 and TRPV1, while TRPV1 has a protective role against skin inflammation in mice.
- Jing Feng
- , Pu Yang
- & Hongzhen Hu
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Article
| Open AccessThermogenetic neurostimulation with single-cell resolution
Current approaches to thermogenetic manipulation of neuronal activity lack sufficient spatiotemporal resolution. Here the authors show that neurons expressing snake TRPA1 channels are activated at high temporal resolution with IR light and this technique can be used to elicit behaviour in zebrafish larvae.
- Yulia G. Ermakova
- , Aleksandr A. Lanin
- & Vsevolod V. Belousov
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Article
| Open AccessAn evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors
N-methyl D-aspartate receptor (NMDAR) activity is modulated by Src tyrosine kinase via the mitochondrial protein NADH dehydrogenase subunit 2 (ND2). Here the authors show that ND2 interacts with the transmembrane region of NMDAR GluN1 subunit, a process that is crucial for Src regulation of NMDAR activity.
- David P. Scanlon
- , Alaji Bah
- & Michael W. Salter
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Article
| Open AccessChemical labelling for visualizing native AMPA receptors in live neurons
Visualizing neurotransmitter receptor traffic is fundamental to understanding brain functions, but the current imaging methods can compromise the process. Here, the authors synthesize small fluorescent probes to label endogenous glutamate receptors in cell cultures and brain tissues, without affecting their function.
- Sho Wakayama
- , Shigeki Kiyonaka
- & Itaru Hamachi
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Article
| Open AccessMechanism of partial agonism in AMPA-type glutamate receptors
Partial agonists weakly activate receptors even when occupying all available binding sites. Here the authors show that partial agonists of the AMPA receptor drive the adoption of multiple inactive forms, accounting for their limited efficacy.
- Hector Salazar
- , Clarissa Eibl
- & Andrew Plested
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Article
| Open AccessThe complete structure of an activated open sodium channel
Voltage-gated sodium (Nav) channels are crucial for action potential initiation in excitable cells. Here the authors present the complete structure of prokaryotic NavMs in a fully open state, providing structural insight into the opening and closure of the channel's intracellular gate.
- Altin Sula
- , Jennifer Booker
- & B. A. Wallace