Ion channels in the nervous system

  • Article
    | Open Access

    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
    | Open Access

    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
  • Article
    | Open Access

    Currently, bidirectional control of activity in the same neurons in the same experiment is difficult. Here the authors report a Bidirectional Pair of Opsins for Light-induced Excitation and Silencing, BiPOLES, which they use in a range of organisms including worms, fruit flies, mice and ferrets.

    • Johannes Vierock
    • , Silvia Rodriguez-Rozada
    •  & J. Simon Wiegert
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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