Ion channels 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
  05 April 2024 | Open Access

  Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms

  Pannexins are large pore channels involved in ion and ATP release. Here the authors use cryo-EM structures of Pannexins 1 and 3 to demonstrate the effects of distinct residue substitutions on channel structure and function.

  • Nazia Hussain
  • , Ashish Apotikar
  •  & Aravind Penmatsa

• Article
  30 March 2024 | Open Access

  Structural bases of inhibitory mechanism of Ca_V1.2 channel inhibitors

  CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.

  • Yiqing Wei
  • , Zhuoya Yu
  •  & Yan Zhao

• 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
  20 March 2024 | Open Access

  Structure of an open K_ATP channel reveals tandem PIP₂ binding sites mediating the Kir6.2 and SUR1 regulatory interface

  K_ATP channels regulate insulin secretion and are activated by PIP₂. Here, the authors show PIP₂ binds between SUR1 and Kir6.2 to open the channel, and a neonatal diabetes mutation stabilizes K_ATP channels in a PIP₂-bound open conformation.

  • Camden M. Driggers
  • , Yi-Ying Kuo
  •  & Show-Ling Shyng

• Article
  14 March 2024 | Open Access

  Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin

  The poison dart toxin batrachotoxin is the most lethal voltage-gated sodium channel toxin. Here authors identify the toxin bound specifically at two homologous receptor sites, which cause channel hyperactivation by positively modulating channel gating and altering ion conductance.

  • Lige Tonggu
  • , Goragot Wisedchaisri
  •  & William A. Catterall

• Article
  07 March 2024 | Open Access

  Chloride intracellular channel (CLIC) proteins function as fusogens

  The Chloride Intracellular Channel (CLIC) protein family is highly conserved, yet their function remains a matter of ongoing research. Here, authors reveal their ability to facilitate membrane fusion, shedding light on their physiological role.

  • Bar Manori
  • , Alisa Vaknin
  •  & Yoni Haitin

• 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
  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
  29 January 2024 | Open Access

  A 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

• Article
  02 January 2024 | Open Access

  Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel

  The authors show that lipid nanodiscs of different scaffold type and size alter the structure of the pentameric ligand-gated ion channel, ELIC. The results suggest that nanodisc selection is an important consideration for structural studies of membrane proteins.

  • Vikram Dalal
  • , Mark J. Arcario
  •  & Wayland W. L. Cheng

• Article
  02 January 2024 | Open Access

  Selective blockade of Ca_v1.2 (α1C) versus Ca_v1.3 (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 Ca_v1.2 L-type Ca²⁺ channels.

  • Pietro Mesirca
  • , Jean Chemin
  •  & Joël Nargeot

• Article
  19 December 2023 | Open Access

  Voltage sensors of a Na⁺ channel dissociate from the pore domain and form inter-channel dimers in the resting state

  It is believed that voltage sensor domains (VSD) of voltage-gated Na+ channels are always attached to the channel. Here, authors find that VSDs detach from the channel to form inter-channel dimers.

  • Ayumi Sumino
  • , Takashi Sumikama
  •  & Katsumasa Irie

• Article
  11 December 2023 | Open Access

  Elucidation 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

• Article
  28 November 2023 | Open Access

  Structural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane

  Bacterial Rhs proteins constitute a diverse family of secreted toxins. Here, the authors present a cryo-electron microscopy structure of an Rhs protein from Pseudomonas aeruginosa and provide insights into the mechanisms by which the protein delivers its encapsulated pore-forming toxin fragment to the bacterial membrane.

  • Amaia González-Magaña
  • , Igor Tascón
  •  & David Albesa-Jové

• Article
  18 November 2023 | Open Access

  Mechanically-primed voltage-gated proton channels from angiosperm plants

  The authors describe a proton channel protein in the vasculature of Arabidopsis thaliana that requires both mechanical and electrical stimuli to turn on. A mechanistic analysis identifies the molecular determinants for the hybrid activation process.

  • Chang Zhao
  • , Parker D. Webster
  •  & Francesco Tombola

• Article
  14 November 2023 | Open Access

  Cryo-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

• Article
  09 November 2023 | Open Access

  Cryo-EM structure of TMEM63C suggests it functions as a monomer

  TMEM63s are mechanosensitive ion channels activated by hypo-osmolality. Here, the authors determine the cryo-EM structure of mouse TMEM63C confirming its predominant monomeric state and the significance of TM0-TM6 coupling in channel activity.

  • Yuqi Qin
  • , Daqi Yu
  •  & Shangyu Dang

• Article
  09 November 2023 | Open Access

  Progesterone 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

• Article
  08 November 2023 | Open Access

  Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms

  Magnesium homeostasis is key for cellular functions. Here, authors report structures of human mitochondrial Mg²⁺ channel MRS2 and identified key residues in gating. This work provides insights into the gating and regulatory mechanisms of MRS2.

  • Louis Tung Faat Lai
  • , Jayashree Balaraman
  •  & Doreen Matthies

• Article
  30 October 2023 | Open Access

  An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1

  The intermembrane complexes mediating calcium signals are crucial but poorly understood. Here the authors identify a Phe-His pair in the calcium-sensing STIM1 protein that controls both activation and pairing of STIM1 with Orai channels to generate calcium signals

  • Yandong Zhou
  • , Michelle R. Jennette
  •  & Donald L. Gill

• Article
  28 October 2023 | Open Access

  Structural titration reveals Ca²⁺-dependent conformational landscape of the IP₃ receptor

  Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are intracellular Ca²⁺ channels that produce Ca²⁺ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP₃Rs that gives rise to the biphasic dependence on Ca²⁺ for channel activity.

  • Navid Paknejad
  • , Vinay Sapuru
  •  & Richard K. Hite

• 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
  19 October 2023 | Open Access

  Ligand activation mechanisms of human KCNQ2 channel

  The potassium channel KCNQ2 can be activated by analgesics and antiepileptic drugs via an unclear mechanism. Here authors report structures of KCNQ2-CaM in complex with cannabidiol, PIP2, and HN37 and elucidate the mechanisms of activation.

  • Demin Ma
  • , Yueming Zheng
  •  & Jiangtao Guo

• Article
  18 October 2023 | Open Access

  Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization

  Voltage sensing of ion channels relies on charged transmembrane helices. Here authors use live-cell FLIM-FRET and nonsense suppression-mediated fluorescence labeling to reveal that voltage sensors undergo direct modulation by compartmentalized membrane domains.

  • Lucas J. Handlin
  •  & Gucan Dai

• Article
  13 October 2023 | Open Access

  Structural insights into the allosteric inhibition of P2X4 receptors

  Cryo-EM structures revealed how chemical compounds bind to and inhibit P2X4 receptors involved in neuropathic pain, potentially facilitating the design of drugs targeting P2X4 receptors.

  • Cheng Shen
  • , Yuqing Zhang
  •  & Motoyuki Hattori

• 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
  21 September 2023 | Open Access

  Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A

  Long-chain acyl-Coenzyme-A is a metabolic intermediate with important signaling functions. Here the authors show that it activates the Ca²⁺ selective ion channels TRPV5 and TRPV6 and elucidate the structural basis of TRPV5 activation using CryoEM.

  • Bo-Hyun Lee
  • , José J. De Jesús Pérez
  •  & Tibor Rohacs

• Article
  20 September 2023 | Open Access

  Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

  P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.

  • Chang-Run Guo
  • , Zhong-Zhe Zhang
  •  & Ye Yu

• Article
  04 September 2023 | Open Access

  DNA nanopores as artificial membrane channels for bioprotonics

  Synthetic membrane channels have many potential applications, but interfacing membrane channels with electronic devices for efficient information transfer is challenging. Here the authors integrate membrane spanning DNA nanopores with bioprotonic contacts to create programmable, modular, and efficient artificial ion-channel interfaces.

  • Le Luo
  • , Swathi Manda
  •  & Marco Rolandi

• 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
  12 August 2023 | Open Access

  Identification 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

• Article
  08 August 2023 | Open Access

  Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn²⁺ uptake into the Golgi apparatus

  ZnT7 is a Golgi-localized Zn2 + /H+ antiporter. Here the authors present the cryo-EM structures of human ZnT7 in Zn2 + -bound and unbound forms, shedding light on its mechanism of Zn2+ transport.

  • Han Ba Bui
  • , Satoshi Watanabe
  •  & Kenji Inaba

• Article
  02 August 2023 | Open Access

  Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

  Neuberger et al. report the structure of human channel TRPV6 in complex with a cannabinoid inhibitor tetrahydrocannabivarin (THCV) and explore the pathway taken by the drug to reach binding sites in the portals that connect the membrane environment to the central cavity of the ion channel pore.

  • Arthur Neuberger
  • , Yury A. Trofimov
  •  & Alexander I. Sobolevsky

• Article
  28 July 2023 | Open Access

  Subunit gating resulting from individual protonation events in Kir2 channels

  Here, authors introduced negative charges in the transmembrane helices in Kir2.2 channels generating pH-dependent sub-conductances. Molecular dynamics simulations show how protonation results in step-wise alterations of ion pooling and hence conductance, appearing as gated substates.

  • Grigory Maksaev
  • , Michael Bründl-Jirout
  •  & Colin G. Nichols

• Article
  26 July 2023 | Open Access

  Cysteines 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

• Article
  18 July 2023 | Open Access

  Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel

  Hu et al. present eight cryo-EM structures of the human cone photoreceptor CNGA3/CNGB3 channel in the closed, intermediate, pre-open and open states, all fully bound with cGMP. These structures provide an unprecedented view of the conformational trajectory of CNG channel activation.

  • Zhengshan Hu
  • , Xiangdong Zheng
  •  & Jian Yang

• Article
  15 July 2023 | Open Access

  The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel

  Divalent cation block is observed in various tetrameric ion channels. Here, authors use X-ray crystallography, electrophysiology and molecular dynamics simulations to reveal the mechanism of the divalent cation block on a prokaryotic sodium channel.

  • Katsumasa Irie
  • , Yoshinori Oda
  •  & Yoshinori Fujiyoshi

• Article
  13 July 2023 | Open Access

  Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity

  An integrated structural biology approach uncovers the structural complexity of the intrinsically disordered region (IDR) within the TRPV4 ion channel. Multiple stimulatory and inhibitory elements were identified within the IDR that modulate channel activity in a lipid-dependent manner.

  • Benedikt Goretzki
  • , Christoph Wiedemann
  •  & Ute A. Hellmich

• Article
  04 July 2023 | Open Access

  A mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity

  Mechanosensitive channels exhibit large structural variations. Here, the authors reveal that OSCA channels exhibit different oligomeric states and are gated/regulated by lipids at different locations in response to physical forces.

  • Mingfeng Zhang
  • , Yuanyue Shan
  •  & Duanqing Pei

• Article
  28 June 2023 | Open Access

  Structure 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

• Article
  23 June 2023 | Open Access

  TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease

  Despite TRPV4’s medical importance, the mechanisms of ligand-mediated channel gating and its regulation by Rho GTPase are unclear. Here, the authors report the structures of TRPV4 in complex with RhoA and ligands, offering atomic-level insights into their functions.

  • Do Hoon Kwon
  • , Feng Zhang
  •  & Seok-Yong Lee

• Article
  23 June 2023 | Open Access

  Structure of human TRPV4 in complex with GTPase RhoA

  Nadezhdin et al. present structures of human TRPV4 in complex with the GTPase RhoA, in the apo, agonist 4α-PDD and antagonist HC-067047 bound states, uncovering the mechanisms of channel activation, inhibition and disease-causing mutations.

  • Kirill D. Nadezhdin
  • , Irina A. Talyzina
  •  & Alexander I. Sobolevsky

• Article
  22 June 2023 | Open Access

  The ER calcium channel Csg2 integrates sphingolipid metabolism with autophagy

  Sphingolipids can function as lipid signaling molecules. Here, the authors find that the endoplasmic reticulum calcium channel Csg2 integrates sphingolipid metabolism with autophagy by regulating calcium homeostasis in endoplasmic reticulum.

  • Shiyan Liu
  • , Mutian Chen
  •  & Kefeng Lu

• Article
  17 June 2023 | Open Access

  Cannabidiol inhibits Na_v channels through two distinct binding sites

  Cannabidiol (CBD), the nonpsychoactive component in cannabis, is an effective treatment for epilepsy and pain. Here, authors explored the mode of action of CBD on hNa_v1.7 channels through two distinct binding sites, suggesting a direct stabilization of the inactivated state of channels.

  • Jian Huang
  • , Xiao Fan
  •  & Nieng Yan

• Article
  17 June 2023 | Open Access

  The inhibition mechanism of the SUR2A-containing K_ATP channel by a regulatory helix

  Cardiac KATP channels consisting of SUR2A are poorly activated by Mg-ADP compared to other subtypes. Here, the authors present structures of SUR2A and SUR2B, uncovering a regulatory helix that inhibits SUR2A activation.

  • Dian Ding
  • , Tianyi Hou
  •  & Lei Chen

• Article
  09 June 2023 | Open Access

  Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42

  AK-42 was reported as a specific inhibitor of ClC-2 but its working mechanism is not clear. Here authors report cryo-EM structures of apo ClC-2 and in complex with AK-42, revealing how it inhibits ClC-2 specifically.

  • Tao Ma
  • , Lei Wang
  •  & Huawei Zhang

• Article
  06 June 2023 | Open Access

  Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

  Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.

  • Rían W. Manville
  • , J. Alfredo Freites
  •  & Geoffrey W. Abbott

• Article
  03 June 2023 | Open Access

  Structural mapping of Na_v1.7 antagonists

  Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels.

  • Qiurong Wu
  • , Jian Huang
  •  & Nieng Yan