Ion channels in the nervous system articles within Nature Communications

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• Article
  11 April 2024 | Open Access

  Tension activation of mechanosensitive two-pore domain K+ channels TRAAK, TREK-1, and TREK-2

  TRAAK, TREK-1 and TREK-2 are mechanosensitive potassium channels involved in action potential propagation among other roles. Here, authors quantify their tension response and show ultrasound can generate tension to activate ion channels.

  • Ben Sorum
  • , Trevor Docter
  •  & Stephen G. Brohawn

• Article
  21 March 2024 | Open Access

  The binding and mechanism of a positive allosteric modulator of Kv3 channels

  To promote the development of effective small molecule modulators that may help treat diverse neuropsychiatric disorders, this study elucidates the mechanism of a specific positive modulator of neuronal potassium channels at near-atomic resolution.

  • Qiansheng Liang
  • , Gamma Chi
  •  & Manuel Covarrubias

• Article
  28 February 2024 | Open Access

  Dendritic mGluR2 and perisomatic Kv3 signaling regulate dendritic computation of mouse starburst amacrine cells

  How starburst amacrine cell (SAC) dendrites transform concentrically distributed synaptic inputs into branch-specific directional outputs is not fully understood. Here the authors report that dendritic mGluR2 signaling and somatic Kv3-mediated shunting coordinately implement SAC dendritic direction selectivity.

  • Héctor Acarón Ledesma
  • , Jennifer Ding
  •  & Wei Wei

• Article
  27 February 2024 | Open Access

  A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor

  Authors show that agonist binding to the muscle acetylcholine receptor releases local conformational heterogeneity transitioning all subunits into a symmetric open state. A release of conformational heterogeneity underlies allosteric communication.

  • Mackenzie J. Thompson
  • , Farid Mansoub Bekarkhanechi
  •  & John E. Baenziger

• Article
  21 February 2024 | Open Access

  Cortical astrocyte N-methyl-D-aspartate receptors influence whisker barrel activity and sensory discrimination in mice

  The role of astrocyte NMDA receptor signaling in cortical circuits is unclear. Here, the authors show that NMDA receptors contribute to astrocyte calcium events and support neuronal processing of sensory information that maintains sensory activity in mice.

  • Noushin Ahmadpour
  • , Meher Kantroo
  •  & Jillian L. Stobart

• Article
  13 February 2024 | Open Access

  The structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels

  The structural basis of membrane permeabilization by Alzheimer’s disease-related amyloid β (Aβ) peptides is elucidated. Membrane insertion of tyrosine-10 supports the most effective ionic conductance of the full-length Aβ_1-42 compared to other isoforms.

  • Abhijith G. Karkisaval
  • , Rowan Hassan
  •  & Suren A. Tatulian

• Article
  07 February 2024 | Open Access

  Photolipid excitation triggers depolarizing optocapacitive currents and action potentials

  Inspired by thermal optocapacitive approaches at regulating neuronal activity, the authors explore a photolipid-based non-thermal optocapacitive method that allows for regulating voltage-gated and mechanosensitive ion channels using light.

  • Carlos A. Z. Bassetto Jr
  • , Juergen Pfeffermann
  •  & Peter Pohl

• Article
  11 December 2023 | Open Access

  Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

  CDKL5 deficiency disorder is one of the most common genetic forms of epilepsy. Here the authors show that a model of CDKL5 deficiency disorder involves a channelopathy of CACNA1E gain-of-function, molecularly linking two distinct single-gene developmental and epileptic encephalopathies.

  • Marisol Sampedro-Castañeda
  • , Lucas L. Baltussen
  •  & Sila K. Ultanir

• Article
  26 October 2023 | Open Access

  GSG1L-containing AMPA receptor complexes are defined by their spatiotemporal expression, native interactome and allosteric sites

  TARPs and GSG1L are evolutionarily- and structurally-related AMPA receptor auxiliary subunits that differ in function through unresolved mechanisms. Here, the authors provide insight into the spatiotemporal expression, composition, and functionality of GSG1L-containing protein complexes.

  • Amanda M. Perozzo
  • , Jochen Schwenk
  •  & Derek Bowie

• Article
  11 October 2023 | Open Access

  Asymmetric 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

• Article
  05 October 2023 | Open Access

  The proton channel OTOP1 is a sensor for the taste of ammonium chloride

  Ammonium is detected by chemosensory systems of humans and other animals to guide avoidance or attractive behavior. Here, the authors show that the proton channel OTOP1 is activated by ammonium, is required for ammonium taste responses in mice, and identify a conserved residue involved in ammonium sensitivity.

  • Ziyu Liang
  • , Courtney E. Wilson
  •  & Emily R. Liman

• Article
  25 September 2023 | Open Access

  An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies

  The α7 nicotinic receptor mediates neuronal communication in the brain. Here, the authors present cryo-EM structures of α7 in complex with single-chain antibodies, revealing an original mechanism of potentiation useful for the design of pro-cognitive drugs.

  • Marie S. Prevost
  • , Nathalie Barilone
  •  & Pierre-Jean Corringer

• Article
  07 September 2023 | Open Access

  Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels

  Neuroinflammation is a common feature of many neurological disorders. Here, the authors show that the Orai1 calcium channel functions as a signaling hub in astrocytes to control astrocyte-driven brain inflammation and inflammation-induced depression-like behaviors in mice.

  • Michaela M. Novakovic
  • , Kirill S. Korshunov
  •  & Murali Prakriya

• Article
  26 August 2023 | Open Access

  Neuronal ER-plasma membrane junctions couple excitation to Ca²⁺-activated PKA signaling

  A-kinase anchoring proteins (AKAPs) target protein kinase A to specific locations within the cell. Here, the authors identify SPHKAP as an AKAP that enriches protein kinase A near ER-plasma membrane contact sites in brain neurons.

  • Nicholas C. Vierra
  • , Luisa Ribeiro-Silva
  •  & James S. Trimmer

• Article
  22 August 2023 | Open Access

  Structural insights into opposing actions of neurosteroids on GABA_A receptors

  Legesse et al. present structural studies of a human GABAA receptor in complex with positive and negative modulator neurosteroids, uncovering mechanisms of potentiation and inhibition.

  • Dagimhiwat H. Legesse
  • , Chen Fan
  •  & Ryan E. Hibbs

• Article
  21 August 2023 | Open Access

  A 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

• Article
  28 July 2023 | Open Access

  NPC1-dependent alterations in K_V2.1–Ca_V1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease

  The molecular mechanisms connecting Niemann Pick C1 cholesterol transporter (NPC1) loss to Niemann-Pick Type C neuropathology remain unknown. Here, the authors demonstrate that loss of NPC1 function alters the nanoscale distribution and function of ion channels to promote abnormal calcium entry, mitochondrial dysfunction, and neurotoxicity.

  • Maria Casas
  • , Karl D. Murray
  •  & Eamonn J. Dickson

• Article
  01 June 2023 | Open Access

  Structural interplay of anesthetics and paralytics on muscle nicotinic receptors

  Here the authors use a structural approach to reveal how neuromuscular blockers and a general anesthetic antagonize the muscle-type nicotinic receptor through competitive and allosteric mechanisms.

  • Umang Goswami
  • , Md Mahfuzur Rahman
  •  & Ryan E. Hibbs

• Article
  19 May 2023 | Open Access

  Molecular mechanism of hyperactivation conferred by a truncation of TRPA1

  A drastic TRPA1 mutant was identified in patients with CRAMPT syndrome, but it has not been functionally characterized. Here, the authors find this mutant confers gain-of-function by co-assembling with wild type protein to form hyperactive channels.

  • Avnika Bali
  • , Samantha P. Schaefer
  •  & Candice E. Paulsen

• Article
  11 May 2023 | Open Access

  Two 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

• Article
  28 April 2023 | Open Access

  Pain-causing stinging nettle toxins target TMEM233 to modulate Na_V1.7 function

  Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of Na_V1.7.

  • Sina Jami
  • , Jennifer R. Deuis
  •  & Irina Vetter

• Article
  06 April 2023 | Open Access

  All-optical closed-loop voltage clamp for precise control of muscles and neurons in live animals

  Optogenetic actuation regimes are often static, which allows perturbation, but not true control of neuronal activity. Here, the authors describe an all-optical method for bidirectional steering of membrane potential, in closed loop, in C. elegans muscles and neurons, and rat hippocampal slice culture. The ‘optogenetic voltage clamp’ uses two microbial rhodopsin actuators and the rhodopsin voltage indicator QuasAr.

  • Amelie C. F. Bergs
  • , Jana F. Liewald
  •  & Alexander Gottschalk

• Article
  04 April 2023 | Open Access

  Astrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice

  Astrocytes act as a dynamic Cl⁻ reservoir regulating Cl⁻ homeostasis in the CNS. Astrocytic Cl⁻ is high and stable during sleep, it is lower during wakefulness and fluctuates in response to sensory input and motor activity. Efflux of Cl⁻ from astrocytes supports inhibitory transmission in the CNS.

  • Verena Untiet
  • , Felix R. M. Beinlich
  •  & Maiken Nedergaard

• Article
  25 March 2023 | Open Access

  Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

  AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.

  • Danyang Zhang
  • , Remigijus Lape
  •  & Ingo H. Greger

• Article
  01 March 2023 | Open Access

  Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome

  Angelman syndrome (AS) is a neurogenetic disorder. Here, the authors found that PIEZO2 activity is reduced in sensory neurons from a mouse model of AS and used a linoleic acid-enriched diet to enhance PIEZO2 function and ameliorate AS-associated gait deficits.

  • Luis O. Romero
  • , Rebeca Caires
  •  & Julio F. Cordero-Morales

• Article
  24 January 2023 | Open Access

  Rabphilin-3A undergoes phase separation to regulate GluN2A mobility and surface clustering

  GluN2A and GluN2B, two predominant Glu2N subunits of NMDARs in hippocampus and cortex, display distinct organization and mobility in the neuronal surface. Here, authors show Rph3A, a GluN2A-specific binding protein, undergoes liquid-liquid phase separation, which regulate mobility, synaptic and extrasynaptic surface clustering, synaptic localization and synaptic response of GluN2A.

  • Lei Yang
  • , Mengping Wei
  •  & Chen Zhang

• Comment
  09 December 2022 | Open Access

  Regulating voltage-gated ion channels with nanobodies

  In this work, Morgenstern and colleagues describe an approach involving functionalized nanobodies which decrease the activity of voltage-gated Ca²⁺ channels associated with β₁ subunits and promote their removal from the surface membrane of neurons and muscle.

  • Declan Manning
  •  & L. Fernando Santana

• Article
  09 December 2022 | Open Access

  Selective posttranslational inhibition of Ca_Vβ₁-associated voltage-dependent calcium channels with a functionalized nanobody

  Auxiliary subunit molecular diversity is an unexploited target for developing ion channel inhibitors. Here, the authors develop a general approach to inhibit ion channels based on the resident auxiliary subunit isoform to elucidate unique functions of distinct ion channel macromolecular complexes.

  • Travis J. Morgenstern
  • , Neha Nirwan
  •  & Henry M. Colecraft

• Article
  05 December 2022 | Open Access

  Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

  TRPV2 is activated by temperature and cannabinoids. Here, the authors have used cryo-EM and electrophysiology to identify a cannabinoid binding site distinct from that of cannabidiol as a possible drug target for treatment of inflammation and immune-mediated diseases.

  • Liying Zhang
  • , Charlotte Simonsen
  •  & Peter M. Zygmunt

• Article
  22 October 2022 | Open Access

  TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine

  A mouse model of chronic migraine reveals that males recover normal sensitivity before than females. This antinociception requires TRPM8 expression and presence of testosterone, which elicits currents and calcium transients via human and murine TRPM8.

  • David Alarcón-Alarcón
  • , David Cabañero
  •  & Antonio Ferrer-Montiel

• Article
  17 October 2022 | Open Access

  The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain

  The authors report how the cold and heat sensing properties of the pain receptor TRPA1 are separately modulated by the C-terminal intracellular domain, and in concert with either the S1–S4 or the S5–S6 transmembrane domain.

  • Lavanya Moparthi
  • , Viktor Sinica
  •  & Peter M. Zygmunt

• Article
  18 August 2022 | Open Access

  Structural 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

• Article
  17 August 2022 | Open Access

  Cryo-EM structures of the channelrhodopsin ChRmine in lipid nanodiscs

  ChRmine is a bacteriorhodopsin-like cation channelrhodopsin (BCCR). Here, the authors present cryo-EM structures of ChRmine in apo- and retinal-bound forms to provide insight into channel activity in a BCCR and facilitate engineering of ChRmine-based optogenetic tools.

  • Kyle Tucker
  • , Savitha Sridharan
  •  & Stephen G. Brohawn

• Article
  06 August 2022 | Open Access

  Structural and dynamic mechanisms of GABA_A receptor modulators with opposing activities

  GABA_A receptors are important targets for anxiety, sedation and anesthesia. Here, the authors present structures bound by zolpidem (Ambien), the most prescribed hypnotic in the US, and DMCM, a negative modulator, providing insights into receptor modulation.

  • Shaotong Zhu
  • , Akshay Sridhar
  •  & Ryan E. Hibbs

• Comment
  15 July 2022 | Open Access

  Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain

  Kv3 channels enable neurons to fire at very high frequencies (>100 Hz) which is fundamental to brain development and our ability to make sense of the world at large. Cryo-EM and structure-function studies by Chi et al. now uncover Kv3 channel gating mechanisms and support new precision medicine approaches for CNS diseases.

  • Martin J. Gunthorpe

• Article
  15 July 2022 | Open Access

  Inhibition of NMDA receptors through a membrane-to-channel path

  Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.

  • Madeleine R. Wilcox
  • , Aparna Nigam
  •  & Jon W. Johnson

• Article
  02 July 2022 | Open Access

  Humidity response in Drosophila olfactory sensory neurons requires the mechanosensitive channel TMEM63

  Humidity detection is a feature of many species. Here the authors show that in Drosophila, Or42b neurons, located in sensilla with humidity-dependent shape act as humidity sensors via the mechanically gated channel TMEM63.

  • Songling Li
  • , Bingxue Li
  •  & Zhiqiang Yan

• Article
  09 June 2022 | Open Access

  Structural 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

• Article
  12 May 2022 | Open Access

  Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex

  NALCN channel mediates sodium leak currents and is essential for neuronal activity. Here authors uncover the mechanism of how UNC79 and UNC80 interact and promote the function of NALCN channel.

  • Yunlu Kang
  •  & Lei Chen

• Article
  15 March 2022 | Open Access

  Intrinsically 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

• Article
  17 February 2022 | Open Access

  Nanoscale rules governing the organization of glutamate receptors in spine synapses are subunit specific

  Glutamate receptors comprise two obligate subunits and two subunits that confer distinct properties and functions to the specific tetramers, which also localize to distinct synaptic spines. Here, the authors use STimulated Emission Depletion nanoscopy (STED) to provide detailed insights into the spatial organization of glutamate receptor types.

  • Martin Hruska
  • , Rachel E. Cain
  •  & Matthew B. Dalva

• Article
  17 February 2022 | Open Access

  Development and characterization of functional antibodies targeting NMDA receptors

  Selective targeting individual subtypes of N-methyl-D-aspartate receptors (NMDARs) is a desirable therapeutic strategy for neurological disorders. Here, the authors report identification of a functional antibody that specifically targets and allosterically down-regulates ion channel activity of the GluN1—GluN2B NMDAR subtype.

  • Nami Tajima
  • , Noriko Simorowski
  •  & Hiro Furukawa

• Article
  10 February 2022 | Open Access

  Structures 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

• Article
  08 February 2022 | Open Access

  Mechanisms 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

• Article
  25 January 2022 | Open Access

  Focused ultrasound excites cortical neurons via mechanosensitive calcium accumulation and ion channel amplification

  The mechanisms underlying the effects of ultrasonic modulation of neural activity are unclear. Here, the authors show that focused ultrasound excites cultured primary murine cortical neurons via calcium accumulation through specific mechanosensitive ion channels.

  • Sangjin Yoo
  • , David R. Mittelstein
  •  & Mikhail G. Shapiro

• Article
  24 November 2021 | Open Access

  Trpm5 channels encode bistability of spinal motoneurons and ensure motor control of hindlimbs in mice

  The authors show that Trpm5, but not Trpm4, is the main Na+ -permeant channel mediating the warmth-activated ICaN in lumbar motoneurons. Trpm5 is also critical in generating plateau potentials in bistable motoneurons that are essential for producing a postural tone in hindlimbs and amplifying the locomotor output.

  • Rémi Bos
  • , Benoît Drouillas
  •  & Frédéric Brocard

• Article
  19 November 2021 | Open Access

  Resurgent Na⁺ currents promote ultrafast spiking in projection neurons that drive fine motor control

  The zebra finch robust nucleus of the arcopallium (RA) directs singing by providing descending projections to brainstem motor neurons. The authors show that electrophysiological characteristics of RA neurons rely on resurgent Na+ currents that emerge early during song development only in males.

  • Benjamin M. Zemel
  • , Alexander A. Nevue
  •  & Henrique von Gersdorff

• Article
  23 August 2021 | Open Access

  AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions

  Changes in AMPAR localization can control the strength of synaptic transmission. Here, the authors show that the interactions of TARP γ8 and the AMPAR N-terminal domain work together to regulate receptor accumulation and positioning at the post-synapse of mouse hippocampal CA1 neurons.

  • Jake F. Watson
  • , Alexandra Pinggera
  •  & Ingo H. Greger

• Article
  10 August 2021 | Open Access

  Place fields of single spikes in hippocampus involve Kcnq3 channel-dependent entrainment of complex spike bursts

  Hippocampal pyramidal cells encode an animal’s location by single action potentials and complex spike bursts. The authors show that Kcnq3-containing M-channels synergistically with GABAergic inputs coordinate complex spike bursts during theta oscillations, which is a key mechanism for spatial coding by single spikes.

  • Xiaojie Gao
  • , Franziska Bender
  •  & Alexey Ponomarenko

• Article
  05 August 2021 | Open Access

  GluN2A and GluN2B NMDA receptors use distinct allosteric routes

  NMDA receptors are glutamate-gated ion channels essential for synapse maturation and plasticity. Here the authors show that GluN2A and GluN2B NMDA receptors — the two principal subtypes NMDARs in the adult CNS — operate through distinct long range allosteric mechanisms.

  • Meilin Tian
  • , David Stroebel
  •  & Pierre Paoletti