The Experts below are selected from a list of 17499 Experts worldwide ranked by ideXlab platform
Thomas V Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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kcne1 binds to the kcnq1 pore to regulate Potassium channel activity
Neuron, 2004Co-Authors: Yonathan F Melman, Sung Yon Um, Andrew Krumerman, Anna Kagan, Thomas V McdonaldAbstract:Abstract Potassium Channels control the resting membrane potential and excitability of biological tissues. Many Voltage-Gated Potassium Channels are controlled through interactions with accessory subunits of the KCNE family through mechanisms still not known. Gating of mammalian channel KCNQ1 is dramatically regulated by KCNE subunits. We have found that multiple segments of the channel pore structure bind to the accessory protein KCNE1. The sites that confer KCNE1 binding are necessary for the functional interaction, and all sites must be present in the channel together for proper regulation by the accessory subunit. Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K + Channels.
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kcne1 binds to the kcnq1 pore to regulate Potassium channel activity
Neuron, 2004Co-Authors: Yonathan F Melman, Sung Yon Um, Andrew Krumerman, Anna Kagan, Thomas V McdonaldAbstract:Abstract Potassium Channels control the resting membrane potential and excitability of biological tissues. Many Voltage-Gated Potassium Channels are controlled through interactions with accessory subunits of the KCNE family through mechanisms still not known. Gating of mammalian channel KCNQ1 is dramatically regulated by KCNE subunits. We have found that multiple segments of the channel pore structure bind to the accessory protein KCNE1. The sites that confer KCNE1 binding are necessary for the functional interaction, and all sites must be present in the channel together for proper regulation by the accessory subunit. Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K + Channels.
Luis A. Pardo - One of the best experts on this subject based on the ideXlab platform.
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Voltage-Gated Potassium Channels as therapeutic targets
Nature Reviews Drug Discovery, 2009Co-Authors: Heike Wulff, Neil A. Castle, Luis A. PardoAbstract:The human genome contains 40 Voltage-Gated Potassium Channels (KV) which are involved in diverse physiological processes ranging from repolarization of neuronal or cardiac action potentials, over regulating calcium signaling and cell volume, to driving cellular proliferation and migration. KV Channels offer tremendous opportunities for the development of new drugs for cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This review first discusses pharmacological strategies for targeting KV Channels with venom peptides, antibodies and small molecules and then highlights recent progress in the preclinical and clinical development of drugs targeting KV1.x, KV7.x (KCNQ), KV10.1 (EAG1) and KV11.1 (hERG) Channels.
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Role of Voltage-Gated Potassium Channels in Cancer
The Journal of Membrane Biology, 2005Co-Authors: Luis A. Pardo, C. Contreras-jurado, M. Zientkowska, F. Alves, W. StühmerAbstract:Ion Channels are being associated with a growing number of diseases including cancer. This overview summarizes data on Voltage-Gated Potassium Channels (VGKCs) that exhibit oncogenic properties: ether-à-go-go type 1 (Eag1). Normally, Eag1 is expressed almost exclusively in tissue of neural origin, but its ectopic expression leads to uncontrolled proliferation, while inhibition of Eag1 expression produces a concomitant reduction in proliferation. Specific monoclonal antibodies against Eag1 recognize an epitope in over 80% of human tumors of diverse origins, endowing it with diagnostic and therapeutic potential. Eag1 also possesses unique electrophysiological properties that simplify its identification. This is particularly important, as specific blockers of Eag1 currents are not available. Molecular imaging of Eag1 in live tumor models has been accomplished with dye-tagged antibodies using 3-D imaging techniques in the near-infrared spectral range.
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voltage gated Potassium Channels in cell proliferation
Physiology, 2004Co-Authors: Luis A. PardoAbstract:It is commonly accepted that cells require K+ Channels to proliferate. The role(s) of K+ Channels in the process is, however, poorly understood. Cloning of K+ channel genes opened the possibility to approach this problem in a way more independent from pharmacological tools. Recent work shows that several identified K+ Channels are important in both physiological and pathological cell proliferation and open a promising pathway for novel targeted therapies.
Yonathan F Melman - One of the best experts on this subject based on the ideXlab platform.
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kcne1 binds to the kcnq1 pore to regulate Potassium channel activity
Neuron, 2004Co-Authors: Yonathan F Melman, Sung Yon Um, Andrew Krumerman, Anna Kagan, Thomas V McdonaldAbstract:Abstract Potassium Channels control the resting membrane potential and excitability of biological tissues. Many Voltage-Gated Potassium Channels are controlled through interactions with accessory subunits of the KCNE family through mechanisms still not known. Gating of mammalian channel KCNQ1 is dramatically regulated by KCNE subunits. We have found that multiple segments of the channel pore structure bind to the accessory protein KCNE1. The sites that confer KCNE1 binding are necessary for the functional interaction, and all sites must be present in the channel together for proper regulation by the accessory subunit. Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K + Channels.
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kcne1 binds to the kcnq1 pore to regulate Potassium channel activity
Neuron, 2004Co-Authors: Yonathan F Melman, Sung Yon Um, Andrew Krumerman, Anna Kagan, Thomas V McdonaldAbstract:Abstract Potassium Channels control the resting membrane potential and excitability of biological tissues. Many Voltage-Gated Potassium Channels are controlled through interactions with accessory subunits of the KCNE family through mechanisms still not known. Gating of mammalian channel KCNQ1 is dramatically regulated by KCNE subunits. We have found that multiple segments of the channel pore structure bind to the accessory protein KCNE1. The sites that confer KCNE1 binding are necessary for the functional interaction, and all sites must be present in the channel together for proper regulation by the accessory subunit. Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K + Channels.
Geoffrey W Abbott - One of the best experts on this subject based on the ideXlab platform.
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Direct neurotransmitter activation of Voltage-Gated Potassium Channels.
Nature Communications, 2018Co-Authors: Rían W. Manville, Maria Papanikolaou, Geoffrey W AbbottAbstract:Voltage-Gated Potassium Channels KCNQ2-5 generate the M-current, which controls neuronal excitability. KCNQ2-5 subunits each harbor a high-affinity anticonvulsant drug-binding pocket containing an essential tryptophan (W265 in human KCNQ3) conserved for >500 million years, yet lacking a known physiological function. Here, phylogenetic analysis, electrostatic potential mapping, in silico docking, electrophysiology, and radioligand binding assays reveal that the anticonvulsant binding pocket evolved to accommodate endogenous neurotransmitters including γ-aminobutyric acid (GABA), which directly activates KCNQ5 and KCNQ3 via W265. GABA, and endogenous metabolites β-hydroxybutyric acid (BHB) and γ-amino-β-hydroxybutyric acid (GABOB), competitively and differentially shift the voltage dependence of KCNQ3 activation. Our results uncover a novel paradigm: direct neurotransmitter activation of Voltage-Gated ion Channels, enabling chemosensing of the neurotransmitter/metabolite landscape to regulate channel activity and cellular excitability.
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Do All Voltage-Gated Potassium Channels Use MiRPs?
2015Co-Authors: Geoffrey W Abbott, Steve A N Goldstein, Federico SestiAbstract:Once again, a MinK-related peptide (MiRP) hasbeen implicated in allowing a pore-forming,Voltage-Gated Potassium channel a subunit to achieve its potential. In this issue of Circulation Research, Zhang et al1 show that MiRP1 (encoded by the KCNE2 gene) can alter the function of Kv4 family subunits (which contribute to Ito, transient outward currents in heart and brain) when they are expressed together in Xenopus oocytes. After recent reports that MiRP1 affects the behavior of HERG2 – 6 and MiRP2 affects the function of KCNQ1, KCNQ4, HERG, and Kv3.4,7,8 the MiRP subunits have been accused of widespread promiscuous partnering. Whether this salacious charge is a valid reflection of natural physiology is the critical issue at hand. MinK and its four recognized relations (MiRP1 through MiRP4 encoded by KCNE1 through KCNE5) are diminu-tive single-transmembrane subunits that coassemble with
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kcne1 and kcne2 inhibit forward trafficking of homomeric n type voltage gated Potassium Channels
Biophysical Journal, 2011Co-Authors: Vikram A Kanda, Xianghua Xu, Anthony Lewis, Geoffrey W AbbottAbstract:Potassium currents generated by Voltage-Gated Potassium (Kv) Channels comprising α-subunits from the Kv1, 2, and 3 subfamilies facilitate high-frequency firing of mammalian neurons. Within these subfamilies, only three α-subunits (Kv1.4, Kv3.3, and Kv3.4) generate currents that decay rapidly in the open state because an N-terminal ball domain blocks the channel pore after activation—a process termed N-type inactivation. Despite its importance to shaping cellular excitability, little is known of the processes regulating surface expression of N-type α-subunits, versus their slowly inactivating (delayed rectifier) counterparts. Here we found that currents generated by homomeric Kv1.4, Kv3.3, and Kv3.4 Channels are all strongly suppressed by the single transmembrane domain ancillary (β) subunits KCNE1 and KCNE2. A combination of electrophysiological, biochemical, and immunofluorescence analyses revealed this suppression is due to KCNE1 and KCNE2 retaining Kv1.4 and Kv3.4 intracellularly, early in the secretory pathway. The retention is specific, requires α-β coassembly, and does not involve the dynamin-dependent endocytosis pathway. However, the small fraction of Kv3.4 that escapes KCNE-dependent retention is regulated by dynamin-dependent endocytosis. The findings illustrate two contrasting mechanisms controlling surface expression of N-type Kv α-subunits and therefore, potentially, cellular excitability and refractory periods.
Jan Tytgat - One of the best experts on this subject based on the ideXlab platform.
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c terminal residues in small Potassium channel blockers odk1 and osk3 from scorpion venom fine tune the selectivity
Biochimica et Biophysica Acta, 2017Co-Authors: Steve Peigneur, Jan Tytgat, Alexey I Kuzmenkov, Anton O Chugunov, Valentin M Tabakmakher, Roman G Efremov, Eugene V Grishin, Alexander A VassilevskiAbstract:We report isolation, sequencing, and electrophysiological characterization of OSK3 (α-KTx 8.8 in Kalium and Uniprot databases), a Potassium channel blocker from the scorpion Orthochirus scrobiculosus venom. Using the voltage clamp technique, OSK3 was tested on a wide panel of 11 Voltage-Gated Potassium Channels expressed in Xenopus oocytes, and was found to potently inhibit Kv1.2 and Kv1.3 with IC50 values of ~331nM and ~503nM, respectively. OdK1 produced by the scorpion Odontobuthus doriae differs by just two C-terminal residues from OSK3, but shows marked preference to Kv1.2. Based on the charybdotoxin-Potassium channel complex crystal structure, a model was built to explain the role of the variable residues in OdK1 and OSK3 selectivity.
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synthesis and characterization of amino acid deletion analogs of κ hefutoxin 1 a scorpion toxin on Potassium Channels
Toxicon, 2013Co-Authors: Steve Peigneur, Jan Tytgat, Yoko Yamaguchi, Hitomi Goto, Kellathur N Srinivasan, P Gopalakrishnakone, Kazuki SatoAbstract:Nine analogs of scorpion toxin peptide κ-hefutoxin 1 were synthesized by stepwise deletion of its amino acid residues. Disulfide bond pairings of the synthetic analogs were confirmed by enzymatic digestion followed by MALDI-TOF-MS measurements. Functional characterization shows that analogs in which N-terminal residues were deleted retained biological activity, whereas deletion of middle part residues resulted in loss of activity. Furthermore, κ-hefutoxin 1 and analogs were subjected to a screening on Voltage-Gated Potassium Channels in order to determine their subtype selectivity. It is shown that κ-hefutoxin 1 is suitable as template for peptidomimetics in order to design small peptide-based therapeutic compounds.
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a bifunctional sea anemone peptide with kunitz type protease and Potassium channel inhibiting properties
Biochemical Pharmacology, 2011Co-Authors: Steve Peigneur, Lászlo Béress, Bert Billen, Rita Derua, Etienne Waelkens, Sarah Debaveye, Jan TytgatAbstract:Abstract Sea anemone venom is a known source of interesting bioactive compounds, including peptide toxins which are invaluable tools for studying structure and function of Voltage-Gated Potassium Channels. APEKTx1 is a novel peptide isolated from the sea anemone Anthopleura elegantissima , containing 63 amino acids cross-linked by 3 disulfide bridges. Sequence alignment reveals that APEKTx1 is a new member of the type 2 sea anemone peptides targeting Voltage-Gated Potassium Channels (K V s), which also include the kalicludines from Anemonia sulcata . Similar to the kalicludines, APEKTx1 shares structural homology with both the basic pancreatic trypsin inhibitor (BPTI), a very potent Kunitz-type protease inhibitor, and dendrotoxins which are powerful blockers of Voltage-Gated Potassium Channels. In this study, APEKTx1 has been subjected to a screening on a wide range of 23 ion Channels expressed in Xenopus laevis oocytes: 13 cloned Voltage-Gated Potassium Channels (K V 1.1–K V 1.6, K V 1.1 triple mutant, K V 2.1, K V 3.1, K V 4.2, K V 4.3, hERG, the insect channel Shaker IR), 2 cloned hyperpolarization-activated cyclic nucleotide-sensitive cation non-selective Channels (HCN1 and HCN2) and 8 cloned Voltage-Gated sodium Channels (Na V 1.2–Na V 1.8 and the insect channel DmNa V 1). Our data show that APEKTx1 selectively blocks K V 1.1 Channels in a very potent manner with an IC 50 value of 0.9 nM. Furthermore, we compared the trypsin inhibitory activity of this toxin with BPTI. APEKTx1 inhibits trypsin with a dissociation constant of 124 nM. In conclusion, this study demonstrates that APEKTx1 has the unique feature to combine the dual functionality of a potent and selective blocker of K V 1.1 Channels with that of a competitive inhibitor of trypsin.
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Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of Voltage-Gated Potassium Channels.
Toxicon, 2008Co-Authors: Eva Cuypers, Yousra Abdel-mottaleb, Ivan Kopljar, Jon D. Rainier, Adam Raes, Dirk J. Snyders, Jan TytgatAbstract:In this study, we pharmacologically characterized gambierol, a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Besides several other polycyclic ether toxins like ciguatoxins, this scarcely studied toxin is one of the compounds that may be responsible for ciguatera fish poisoning (CFP). Unfortunately, the biological target(s) that underlies CFP is still partly unknown. Today, ciguatoxins are described to specifically activate Voltage-Gated sodium Channels by interacting with their receptor site 5. But some dispute about the role of gambierol in the CFP story shows up: some describe Voltage-Gated sodium Channels as the target, while others pinpoint Voltage-Gated Potassium Channels as targets. Since gambierol was never tested on isolated ion Channels before, it was subjected in this work to extensive screening on a panel of 17 ion Channels: nine cloned Voltage-Gated ion Channels (mammalian Nav1.1–Nav1.8 and insect Para) and eight cloned Voltage-Gated Potassium Channels (mammalian Kv1.1–Kv1.6, hERG and insect ShakerIR) expressed in Xenopus laevis oocytes using two-electrode voltage-clamp technique. All tested sodium channel subtypes are insensitive to gambierol concentrations up to 10 μM. In contrast, Kv1.2 is the most sensitive Voltage-Gated Potassium channel subtype with almost full block (>97%) and an half maximal inhibitory concentration (IC50) of 34.5 nM. To the best of our knowledge, this is the first study where the selectivity of gambierol is tested on isolated Voltage-Gated ion Channels. Therefore, these results lead to a better understanding of gambierol and its possible role in CFP and they may also be useful in the development of more effective treatments.
