Ligand-gated ion channels

Ion channels are at the heart of many biological processes such as nerve activity and muscle contraction. How are their impressive ion selectivity and highly specialized gating brought about? In recent years, X-ray crystallography and high-resolution electron microscopy, as well as photo-affinity labeling and site-specific mutagenesis techniques in combination with patch-clamp electrophysiology have provided a detailed picture of some channel proteins. Herein we summarize the main structural and functional properties of channel proteins based on the advances made mainly within the last decade. We integrate these novel insights into a comprehensive description of the class of ligand-gated ion channels.

[1]  R. Dingledine,et al.  Identification of a site in glutamate receptor subunits that controls calcium permeability , 1991, Science.

[2]  Diying Huang,et al.  An early Cambrian craniate-like chordate , 1999, Nature.

[3]  M. Sheng,et al.  Ligand-gated ion channel interactions with cytoskeletal and signaling proteins. , 2000, Annual review of physiology.

[4]  D C Rees,et al.  Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel. , 1998, Science.

[5]  B. Chait,et al.  The structure of the potassium channel: molecular basis of K+ conduction and selectivity. , 1998, Science.

[6]  A. Goldman,et al.  Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein , 1991, Science.

[7]  Terri L. Gilbert,et al.  The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins , 1993, Neuron.

[8]  M. Eisenstein,et al.  How well can molecular modelling predict the crystal structure: the case of the ligand-binding domain of glutamate receptors. , 2000, Trends in pharmacological sciences.

[9]  S. Heinemann,et al.  Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins , 1994, Neuron.

[10]  K. Keay,et al.  Structural motif and characteristics of the extracellular domain of P2X receptors. , 1997, Biochemical and biophysical research communications.

[11]  R. Dingledine,et al.  The glutamate receptor ion channels. , 1999, Pharmacological reviews.

[12]  N. Unwin Acetylcholine receptor channel imaged in the open state , 1995, Nature.

[13]  A. Karlin,et al.  Substituted-cysteine accessibility method. , 1998, Methods in enzymology.

[14]  L. Hood,et al.  Acetylcholine receptor: complex of homologous subunits. , 1980, Science.

[15]  R. North,et al.  Pore dilation of neuronal P2X receptor channels , 1999, Nature Neuroscience.

[16]  F. Hucho,et al.  The emerging three-dimensional structure of a receptor. The nicotinic acetylcholine receptor. , 1996, European journal of biochemistry.

[17]  H. Hirai,et al.  Molecular Determinants of Agonist Discrimination by NMDA Receptor Subunits: Analysis of the Glutamate Binding Site on the NR2B Subunit , 1997, Neuron.

[18]  S. Sine,et al.  Molecular Dissection of Subunit Interfaces in the Acetylcholine Receptor , 1996, The Journal of Biological Chemistry.

[19]  R. Beroukhim,et al.  Ultrastructure of the 5‐Hydroxytryptamine3 Receptor , 1995, Journal of neurochemistry.

[20]  S. Rhee,et al.  Molecular Cloning, Splice Variants, Expression, and Purification of Phospholipase C-4 (*) , 1996, The Journal of Biological Chemistry.

[21]  A. Vincent,et al.  Genes at the junction – candidates for congenital myasthenic syndromes , 1997, Trends in Neurosciences.

[22]  B. Fakler,et al.  Gating of inward-rectifier K+ channels by intracellular pH. , 2000, European journal of biochemistry.

[23]  F. Hucho,et al.  Anionic subsites of the acetylcholinesterase from Torpedo californica: affinity labelling with the cationic reagent N,N‐dimethyl‐2‐phenyl‐aziridinium. , 1990, The EMBO journal.

[24]  Richard J. Evans,et al.  The Role of Positively Charged Amino Acids in ATP Recognition by Human P2X1 Receptors* , 2000, The Journal of Biological Chemistry.

[25]  T. Sixma,et al.  Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors , 2001, Nature.

[26]  R. Huganir,et al.  Phosphorylation of the Nicotinic Acetylcholine Receptor by Protein Tyrosine Kinases a , 1995, Annals of the New York Academy of Sciences.

[27]  A. Malafosse,et al.  A nonsense mutation in the α4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBNI) , 1994, Neurobiology of Disease.

[28]  L. Jan,et al.  Taking Apart the Gating of Voltage-Gated K+ Channels , 2000, Neuron.

[29]  D. Langosch,et al.  Conserved quaternary structure of ligand-gated ion channels: the postsynaptic glycine receptor is a pentamer. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Y. J. Sun,et al.  The structure of glutamine-binding protein complexed with glutamine at 1.94 A resolution: comparisons with other amino acid binding proteins. , 1998, Journal of molecular biology.

[31]  F. Hucho,et al.  The handedness of the subunit arrangement of the nicotinic acetylcholine receptor from Torpedo californica. , 1995, European journal of biochemistry.

[32]  E. Gouaux,et al.  Mechanisms for Activation and Antagonism of an AMPA-Sensitive Glutamate Receptor Crystal Structures of the GluR2 Ligand Binding Core , 2000, Neuron.

[33]  S. Grant,et al.  Proteomic analysis of NMDA receptor–adhesion protein signaling complexes , 2000, Nature Neuroscience.

[34]  R. North,et al.  Identification of amino acid residues contributing to the pore of a P2X receptor , 1997, The EMBO journal.

[35]  A. Nicke,et al.  P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand‐gated ion channels , 1998, The EMBO journal.

[36]  M. Mark,et al.  G-protein mediated gating of inward-rectifier K+ channels. , 2000, European journal of biochemistry.

[37]  Henry A. Lester,et al.  State-dependent cross-inhibition between transmitter-gated cation channels , 2000, Nature.

[38]  Rolf Hilgenfeld,et al.  The selectivity filter of a ligand‐gated ion channel , 1989, FEBS letters.

[39]  C. January,et al.  Internet resources for exploring gene family diversity. , 2000, TIPS - Trends in Pharmacological Sciences.

[40]  D. Kirsch,et al.  Photolabeling reveals the proximity of the alpha-neurotoxin binding site to the M2 helix of the ion channel in the nicotinic acetylcholine receptor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  T. Vorherr,et al.  The calmodulin-binding domain mediates the self-association of the plasma membrane Ca2+ pump. , 1991, The Journal of biological chemistry.

[42]  T. Egan,et al.  Hetero-oligomeric Assembly of P2X Receptor Subunits , 1999, The Journal of Biological Chemistry.

[43]  G. Coruzzi,et al.  Molecular evolution of glutamate receptors: a primitive signaling mechanism that existed before plants and animals diverged. , 1999, Molecular biology and evolution.

[44]  B. Sakmann,et al.  Location of a δ-subunit region determining ion transport through the acetylcholine receptor channel , 1986, Nature.

[45]  K. Keinänen,et al.  Molecular dissection of the agonist binding site of an AMPA receptor. , 1995, The EMBO journal.

[46]  R. Sparkes,et al.  Startle disease, or hyperekplexia: Response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis , 1992, Annals of neurology.

[47]  A. Karlin,et al.  Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the α subunit , 1994, Neuron.

[48]  B. Sakmann,et al.  Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance , 1988, Nature.

[49]  G. Coruzzi,et al.  Glutamate-receptor genes in plants , 1998, Nature.

[50]  B. Sakmann,et al.  Threonine in the selectivity filter of the acetylcholine receptor channel. , 1992, Biophysical journal.

[51]  K. Mikoshiba,et al.  Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  H. Lester,et al.  Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. , 1988, Science.

[53]  A. Karlin,et al.  The Location of the Gate in the Acetylcholine Receptor Channel , 1998, Neuron.

[54]  J. Changeux,et al.  Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: serine-262 of the delta subunit is labeled by [3H]chlorpromazine. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Sine Molecular dissection of subunit interfaces in the acetylcholine receptor: identification of residues that determine curare selectivity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[56]  P. Seeburg,et al.  Transient expression shows ligand gating and allosteric potentiation of GABAA receptor subunits. , 1988, Science.

[57]  Baukrowitz Inward rectifier potassium channels and a multitude of intracellular gating molecules , 2000, European Journal of Biochemistry.

[58]  J. Changeux,et al.  Allosteric transitions of the acetylcholine receptor. , 1998, Advances in protein chemistry.

[59]  Nicolas Le Novère,et al.  The Ligand Gated Ion Channel Database , 1999, Nucleic Acids Res..

[60]  Richard L. Huganir,et al.  GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors , 1997, Nature.

[61]  F. Lottspeich,et al.  The ion channel of the nicotinic acetylcholine receptor is formed by the homologous helices M II of the receptor subunits , 1986 .

[62]  Y. Fujiyoshi,et al.  Nicotinic acetylcholine receptor at 4.6 A resolution: transverse tunnels in the channel wall. , 1999, Journal of molecular biology.

[63]  J. Changeux,et al.  Improved secondary structure predictions for a nicotinic receptor subunit: incorporation of solvent accessibility and experimental data into a two-dimensional representation. , 1999, Biophysical journal.

[64]  Miriam Eisenstein,et al.  Identification of the Amino Acid Subsets Accounting for the Ligand Binding Specificity of a Glutamate Receptor , 1996, Neuron.

[65]  A. Karlin,et al.  Structure of the Nicotinic Receptor Acetylcholine-binding Site , 1995, The Journal of Biological Chemistry.

[66]  Baljit S Khakh,et al.  Dynamic Selectivity Filters in Ion Channels , 1999, Neuron.

[67]  K. Keinänen,et al.  Ligand recognition in glutamate receptors: insights from mutagenesis of the soluble alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-binding domain of glutamate receptor type D (GluR-D). , 1997, Biochemical Society Transactions.

[68]  A. Karlin,et al.  Acetylcholine receptor binding site contains a disulfide cross-link between adjacent half-cystinyl residues. , 1986, The Journal of biological chemistry.

[69]  E. Michaelis Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging , 1998, Progress in Neurobiology.

[70]  Xiaodong Wang,et al.  Nucleotide Requirements for the in Vitro Activation of the Apoptosis Protein-activating Factor-1-mediated Caspase Pathway* , 2000, The Journal of Biological Chemistry.

[71]  J. Changeux,et al.  Stratification of the channel domain in neurotransmitter receptors. , 1993, Current opinion in cell biology.

[72]  C. Bigge Ionotropic glutamate receptors. , 1999, Current opinion in chemical biology.

[73]  A. Vincent,et al.  Molecular targets for autoimmune and genetic disorders of neuromuscular transmission. , 2000, European journal of biochemistry.

[74]  F. Hucho Molecular weight and quaternary structure of the cholinergic receptor protein extracted by detergents from Electrophorus electricus electric tissue , 1973, FEBS letters.

[75]  Jean-Luc Galzi,et al.  Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic , 1992, Nature.

[76]  H. Betz,et al.  Evidence for a Tetrameric Structure of Recombinant NMDA Receptors , 1998, The Journal of Neuroscience.

[77]  J. Changeux,et al.  Chimaeric nicotinic–serotonergic receptor combines distinct ligand binding and channel specificities , 1993, Nature.

[78]  W. Catterall,et al.  Selectivity of cations and nonelectrolytes for acetylcholine-activated channels in cultured muscle cells , 1978, The Journal of general physiology.

[79]  Jean-Luc Galzi,et al.  Neurotransmitter-gated ion channels as unconventional allosteric proteins , 1994 .

[80]  S. Heinemann,et al.  Molecular Neurobiology and Genetics: Investigation of Neural Function and Dysfunction , 1998, Neuron.

[81]  E. Kawashima,et al.  The Cytolytic P2Z Receptor for Extracellular ATP Identified as a P2X Receptor (P2X7) , 1996, Science.

[82]  A. Herrmann,et al.  How do acetylcholine receptor ligands reach their binding sites? , 1999, European journal of biochemistry.

[83]  T. Sixma,et al.  A glia-derived acetylcholine-binding protein that modulates synaptic transmission , 2001, Nature.

[84]  D. A. Dougherty,et al.  The Cationminus signpi Interaction. , 1997, Chemical reviews.

[85]  P. Seeburg The Role of RNA Editing in Controlling Glutamate Receptor Channel Properties , 1996, Journal of neurochemistry.

[86]  Werner Hoch,et al.  Formation of the neuromuscular junction , 1999 .

[87]  D. Osguthorpe,et al.  Modeling of agonist binding to the ligand‐gated ion channel superfamily of receptors , 1990, Proteins.

[88]  P. Seeburg,et al.  RNA editing in brain controls a determinant of ion flow in glutamate-gated channels , 1991, Cell.

[89]  E. Perozo,et al.  Structural rearrangements underlying K+-channel activation gating. , 1999, Science.

[90]  B. Fakler,et al.  Polyamines as gating molecules of inward-rectifier K+ channels. , 2000, European journal of biochemistry.

[91]  A. Nicke,et al.  Molecular determinants of glycine receptor subunit assembly , 1999, The EMBO journal.

[92]  E. Gouaux,et al.  Probing the ligand binding domain of the GluR2 receptor by proteolysis and deletion mutagenesis defines domain boundaries and yields a crystallizable construct , 1998, Protein science : a publication of the Protein Society.

[93]  T. Egan,et al.  A Domain Contributing to the Ion Channel of ATP-Gated P2X2 Receptors Identified by the Substituted Cysteine Accessibility Method , 1998, The Journal of Neuroscience.

[94]  R. North,et al.  Families of ion channels with two hydrophobic segments. , 1996, Current opinion in cell biology.

[95]  B. Fakler,et al.  KATP channels gated by intracellular nucleotides and phospholipids. , 2000, European journal of biochemistry.

[96]  S. Muallem,et al.  The N-terminal domain of the IP3 receptor gates store-operated hTrp3 channels. , 1999, Molecular cell.

[97]  P P Humphrey,et al.  International Union of Pharmacology. XIX. The IUPHAR receptor code: a proposal for an alphanumeric classification system. , 1998, Pharmacological reviews.

[98]  N. Brandon,et al.  GABAA-receptor-associated protein links GABAA receptors and the cytoskeleton , 1999, Nature.

[99]  Lixin Tang,et al.  Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors , 1995, Nature.

[100]  E. Gouaux,et al.  Structure of a glutamate-receptor ligand-binding core in complex with kainate , 1998, Nature.

[101]  P. H. Barry,et al.  M2 pore mutations convert the glycine receptor channel from being anion- to cation-selective. , 2000, Biophysical journal.

[102]  D. Bertrand,et al.  A neuronal nicotinic acetylcholine receptor subunit (α7) is developmentally regulated and forms a homo-oligomeric channel blocked by α-BTX , 1990, Neuron.

[103]  P. Seeburg,et al.  Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. , 1995, Science.

[104]  I. Scheffer,et al.  A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy , 1995, Nature Genetics.

[105]  D. A. Dougherty,et al.  From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[106]  R. North,et al.  Ionic permeability of, and divalent cation effects on, two ATP‐gated cation channels (P2X receptors) expressed in mammalian cells. , 1996, The Journal of physiology.

[107]  N. Nayeem,et al.  Quaternary Structure of the Native GABAA Receptor Determined by Electron Microscopic Image Analysis , 1994, Journal of neurochemistry.

[108]  N. Unwin Nicotinic acetylcholine receptor at 9 A resolution. , 1993, Journal of molecular biology.

[109]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[110]  Eric Gouaux,et al.  Functional characterization of a potassium-selective prokaryotic glutamate receptor , 1999, Nature.

[111]  K. Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Chembiochem : a European journal of chemical biology.

[112]  A. Karlin,et al.  Identification of acetylcholine receptor channel-lining residues in the M1 segment of the beta-subunit. , 1995, Biochemistry.

[113]  Henry A. Lester,et al.  Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds , 1999, Nature Neuroscience.

[114]  J. Changeux,et al.  Mutational Analysis of the Charge Selectivity Filter of the α7 Nicotinic Acetylcholine Receptor , 1999, Neuron.

[115]  R. Huganir,et al.  Protein phosphorylation of ligand-gated ion channels. , 1999, Methods in enzymology.