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Biochimica Et Biophysica Acta Apr 1999The C-terminal domain of the voltage-gated potassium channel Kv2.1 is shown to have a role in channel assembly using dominant negative experiments in Xenopus oocytes.... (Comparative Study)
Comparative Study
The C-terminal domain of the voltage-gated potassium channel Kv2.1 is shown to have a role in channel assembly using dominant negative experiments in Xenopus oocytes. Kv2.1 channel polypeptides were co-expressed with a number of polypeptide fragments of the cytosolic C-terminus and the assembly of functional channel homotetramers quantified electrophysiologically using the two electrode voltage clamp technique. Co-expression of C-terminal polypeptides corresponding to the final 440, 318, 220 and 150 amino acid residues of Kv2.1 all resulted in a significant reduction in the functional expression of the full-length channel. A truncated version of Kv2.1 lacking the final 318 amino acids of the C-terminal domain (Kv2. 11-535) exhibited similar electrophysiological properties to the full-length channel. Co-expression with either the 440 or 318 residue polypeptides resulted in a reduction in the activity of the truncated channel. In contrast, the 220 and 150 residue C-terminal fragments had no effect on Kv2.11-535 activity. These data demonstrate that C-terminal interactions are important for driving Kv2.1 channel assembly and that distinct regions of the C-terminal domain may have differential effects on the formation of functional tetramers.
Topics: Animals; Cytoplasm; Delayed Rectifier Potassium Channels; Female; Gene Expression; Mutation; Oocytes; Patch-Clamp Techniques; Potassium Channels; Potassium Channels, Voltage-Gated; RNA, Complementary; Shab Potassium Channels; Xenopus laevis
PubMed: 10209222
DOI: 10.1016/s0005-2736(99)00021-8 -
Science's STKE : Signal Transduction... Jun 2003Ion channels and the electrical properties they confer on cells are involved in every human characteristic that distinguishes us from the stones in a field. Every... (Review)
Review
Ion channels and the electrical properties they confer on cells are involved in every human characteristic that distinguishes us from the stones in a field. Every perception, thought, movement, and heartbeat depends on electrical signals generated by the activity of ion channels. Early views of the relationship between channel structure and function have undergone substantial modification following the cloning of various ion channels and the determination of the structure of a simple bacterial K channel, the KcsA channel. This review focuses on the relationship between the structure and function of voltage-dependent K channels, covering the molecular bases of channel selectivity, conduction, and gating. The evolution of ion channels in bacteria is discussed, as well as the basis of channel selectivity and conduction in the KcsA channel. More complex channels have evolved molecular "gatekeepers," allowing them to respond to appropriate stimuli by opening, closing, and inactivating.
Topics: Animals; Bacterial Proteins; Humans; Ion Channel Gating; Potassium Channels; Potassium Channels, Voltage-Gated; Structure-Activity Relationship
PubMed: 12824476
DOI: 10.1126/stke.2003.188.re10 -
Current Biology : CB Mar 2001The number, type and distribution of ion channels on a neuron's surface determine its electrical response to stimulation. One way that a cell determines how many... (Review)
Review
The number, type and distribution of ion channels on a neuron's surface determine its electrical response to stimulation. One way that a cell determines how many molecules of each channel type are sent to the surface has been eludicated in a recent study of intrinsic protein transport signals within potassium channels.
Topics: Animals; Biological Transport; Endoplasmic Reticulum; Golgi Apparatus; Kv1.2 Potassium Channel; Kv1.4 Potassium Channel; Kv1.5 Potassium Channel; Potassium Channels; Potassium Channels, Inwardly Rectifying; Potassium Channels, Voltage-Gated; Protein Sorting Signals
PubMed: 11301268
DOI: 10.1016/s0960-9822(01)00111-7 -
Journal of Medicinal Chemistry Nov 2019Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the... (Review)
Review
Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are modulated by extracellular acidosis. They are extensively distributed along the cardiovascular and central nervous systems, and their expression is up- and downregulated in different cancer types, which makes them an attractive therapeutic target. However, TASK channels remain unexplored, and drugs designed to target these channels are poorly selective. Here, we review TASK channels properties and their known blockers and activators, considering the new challenges in ion channels drug design and focusing on the implementation of computational methodologies in the drug discovery process.
Topics: Animals; Drug Design; Drug Discovery; Humans; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Tandem Pore Domain
PubMed: 31260312
DOI: 10.1021/acs.jmedchem.9b00248 -
Journal of Bioenergetics and... Jun 1996High-conductance calcium-activated potassium (maxi-K) channels comprise a specialized family of K+ channels. They are unique in their dual requirement for depolarization... (Review)
Review
High-conductance calcium-activated potassium (maxi-K) channels comprise a specialized family of K+ channels. They are unique in their dual requirement for depolarization and Ca2+ binding for transition to the open, or conducting, state. Ion conduction through maxi-K channels is blocked by a family of venom-derived peptides, such as charybdotoxin and iberiotoxin. These peptides have been used to study function and structure of maxi-K channels, to identify novel channel modulators, and to follow the purification of functional maxi-K channels from smooth muscle. The channel consists of two dissimilar subunits, alpha and beta. The alpha subunit is a member of the slo Ca(2+)-activated K+ channel gene family and forms the ion conduction pore. The beta subunit is a structurally unique, membrane-spanning protein that contributes to channel gating and pharmacology. Potent, selective maxi-K channel effectors (both agonists and blockers) of low molecular weight have been identified from natural product sources. These agents, together with peptidyl inhibitors and site-directed antibodies raised against alpha and beta subunit sequences, can be used to anatomically map maxi-K channel expression, and to study the physiologic role of maxi-K channels in various tissues. One goal of such investigations is to determine whether maxi-K channels represent novel therapeutic targets.
Topics: Amino Acid Sequence; Animals; Charybdotoxin; Diterpenes; Glycosylation; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Large-Conductance Calcium-Activated Potassium Channels; Models, Molecular; Molecular Sequence Data; Muscle, Smooth; Peptides; Potassium Channels; Potassium Channels, Calcium-Activated; Protein Conformation; Scorpion Venoms; Synapses; Triterpenes
PubMed: 8807400
DOI: 10.1007/BF02110699 -
Neurochemical Research Sep 1992MinK is a novel protein which induces an extremely slowly activating potassium channel when expressed in Xenopus oocytes. We discuss the properties and regulation of the... (Review)
Review
MinK is a novel protein which induces an extremely slowly activating potassium channel when expressed in Xenopus oocytes. We discuss the properties and regulation of the current and localization and possible physiological roles of the MinK protein.
Topics: Amino Acid Sequence; Animals; Biophysical Phenomena; Biophysics; Gene Expression Regulation; Membrane Proteins; Molecular Sequence Data; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 1407274
DOI: 10.1007/BF00993262 -
Cold Spring Harbor Symposia on... 1990The cloning and characterization of the voltage-activated Shaker potassium channel gene in Drosophila have led to the identification of structural elements involved in...
The cloning and characterization of the voltage-activated Shaker potassium channel gene in Drosophila have led to the identification of structural elements involved in potassium channel gating. As found for the voltage-activated sodium channel, the S4 segment, located in the conserved core of the protein, plays a central role in voltage-dependent activation. Potassium channels appear to be formed by the assembly of several polypeptides into multisubunit channels. This is directly analogous to the proposed folding of the four internally homologous pseudosubunits of sodium and calcium channels. The amino- and carboxy-terminal regions of Shaker channels are specialized for, and appear to interact in, inactivation gating. This interaction probably includes interaction between subunits, as may be said for the role in inactivation gating of the junction between the carboxyl terminus of the third domain and amino terminus of the fourth domain of sodium channel (Vassilev et al. 1988). The capacity for coassembly in potassium channels extends not only to the alternatively spliced products of the same gene, but also to the products of different genes. Heteromultimeric channels that are formed in this way have kinetic and pharmacological properties that differ from homomultimers of their constituents and, as such, broaden the functional diversity of channels that can be produced by any given number of compatible potassium channel genes.
Topics: Animals; Cloning, Molecular; DNA, Recombinant; Drosophila; Electrophysiology; Ion Channel Gating; Molecular Biology; Mutation; Phenotype; Potassium Channels
PubMed: 2132867
DOI: 10.1101/sqb.1990.055.01.004 -
Science (New York, N.Y.) Dec 1998The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date,...
The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.
Topics: Adult; Animals; Anthracenes; Brain; Ganglia, Sympathetic; Gene Expression; Humans; Indoles; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Kinetics; Neurons; Oocytes; Patch-Clamp Techniques; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Rats; Sympathetic Nervous System; Tetraethylammonium; Xenopus
PubMed: 9836639
DOI: 10.1126/science.282.5395.1890 -
The Journal of General Physiology May 2023External potassium inhibits KCNQ1 channel through a mechanism involving increased occupancy of the filter S0 site by K.
External potassium inhibits KCNQ1 channel through a mechanism involving increased occupancy of the filter S0 site by K.
Topics: KCNQ1 Potassium Channel; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 36961346
DOI: 10.1085/jgp.202313337 -
Nature Feb 2004Voltage-dependent potassium channels are essential for the generation of nerve impulses. Voltage sensitivity is conferred by charged residues located mainly in the...
Voltage-dependent potassium channels are essential for the generation of nerve impulses. Voltage sensitivity is conferred by charged residues located mainly in the fourth transmembrane segment (S4) of each of the four identical subunits that make up the channel. These charged segments relocate when the potential difference across the membrane changes, controlling the ability of the pore to conduct ions. In the crystal structure of the Aeropyrum pernix potassium channel KvAP, the S4 and part of the third (S3B) transmembrane alpha-helices are connected by a hairpin turn in an arrangement termed the 'voltage-sensor paddle'. This structure was proposed to move through the lipid bilayer during channel activation, transporting positive charges across a large fraction of the membrane. Here we show that replacing the first S4 arginine by histidine in the Shaker potassium channel creates a proton pore when the cell is hyperpolarized. Formation of this pore does not support the paddle model, as protons would not have access to a lipid-buried histidine. We conclude that, at hyperpolarized potentials, water and protons from the internal and external solutions must be separated by a narrow barrier in the channel protein that focuses the electric field to a small voltage-sensitive region.
Topics: Animals; Archaea; Electric Conductivity; Ion Channel Gating; Ion Transport; Lipid Bilayers; Models, Biological; Oocytes; Potassium Channels; Protein Structure, Secondary; Protons; Shaker Superfamily of Potassium Channels; Water
PubMed: 14765197
DOI: 10.1038/nature02270