scholarly journals AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 360 ◽  
Author(s):  
Diego B. Orts ◽  
Steve Peigneur ◽  
Laíz Silva-Gonçalves ◽  
Manoel Arcisio-Miranda ◽  
José P. W. Bicudo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cyclic Peptides ◽  
Complex Mixture ◽  
Sea Anemone ◽  
Random Coil ◽  
Cone Snail ◽  
K Channels ◽  
Voltage Gated ◽  
Kv Channels ◽  
Secondary Structure Analysis

Voltage-gated potassium (KV) channels regulate diverse physiological processes and are an important target for developing novel therapeutic approaches. Sea anemone (Cnidaria, Anthozoa) venoms comprise a highly complex mixture of peptide toxins with diverse and selective pharmacology on KV channels. From the nematocysts of the sea anemone Actinia bermudensis, a peptide that we named AbeTx1 was purified and functionally characterized on 12 different subtypes of KV channels (KV1.1–KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; KV11.1; and, Shaker IR), and three voltage-gated sodium channel isoforms (NaV1.2, NaV1.4, and BgNaV). AbeTx1 was selective for Shaker-related K+ channels and is capable of inhibiting K+ currents, not only by blocking the K+ current of KV1.2 subtype, but by altering the energetics of activation of KV1.1 and KV1.6. Moreover, experiments using six synthetic alanine point-mutated analogs further showed that a ring of basic amino acids acts as a multipoint interaction for the binding of the toxin to the channel. The AbeTx1 primary sequence is composed of 17 amino acids with a high proportion of lysines and arginines, including two disulfide bridges (Cys1–Cys4 and Cys2–Cys3), and it is devoid of aromatic or aliphatic amino acids. Secondary structure analysis reveals that AbeTx1 has a highly flexible, random-coil-like conformation, but with a tendency of structuring in the beta sheet. Its overall structure is similar to open-ended cyclic peptides found on the scorpion κ-KTx toxins family, cone snail venoms, and antimicrobial peptides.

scholarly journals KCNE3 Truncation Mutants Reveal a Bipartite Modulation of KCNQ1 K+ Channels

2004 ◽  
Vol 124 (6) ◽  
pp. 759-771 ◽  
Author(s):  
Steven D. Gage ◽  
William R. Kobertz
Keyword(s):  
Amino Acids ◽  
Transmembrane Domain ◽  
Channel Gating ◽  
Terminal Region ◽  
Type I ◽  
Long Qt ◽  
Transmembrane Peptides ◽  
K Channels ◽  
Voltage Gated ◽  
La Luna

The five KCNE genes encode a family of type I transmembrane peptides that assemble with KCNQ1 and other voltage-gated K+ channels, resulting in potassium conducting complexes with varied channel-gating properties. It has been recently proposed that a triplet of amino acids within the transmembrane domain of KCNE1 and KCNE3 confers modulation specificity to the peptide, since swapping of these three residues essentially converts the recipient KCNE into the donor (Melman, Y.F., A. Domenech, S. de la Luna, and T.V. McDonald. 2001. J. Biol. Chem. 276:6439–6444). However, these results are in stark contrast with earlier KCNE1 deletion studies, which demonstrated that a COOH-terminal region, highly conserved between KCNE1 and KCNE3, was responsible for KCNE1 modulation of KCNQ1 (Tapper, A.R., and A.L. George. 2000 J. Gen. Physiol. 116:379–389.). To ascertain whether KCNE3 peptides behave similarly to KCNE1, we examined a panel of NH2- and COOH-terminal KCNE3 truncation mutants to directly determine the regions required for assembly with and modulation of KCNQ1 channels. Truncations lacking the majority of their NH2 terminus, COOH terminus, or mutants harboring both truncations gave rise to KCNQ1 channel complexes with basal activation, a hallmark of KCNE3 modulation. These results demonstrate that the KCNE3 transmembrane domain is sufficient for assembly with and modulation of KCNQ1 channels and suggests a bipartite model for KCNQ1 modulation by KCNE1 and KCNE3 subunits. In this model, the KCNE3 transmembrane domain is active in modulation and overrides the COOH terminus' contribution, whereas the KCNE1 transmembrane domain is passive and reveals COOH-terminal modulation of KCNQ1 channels. We furthermore test the validity of this model by using the active KCNE3 transmembrane domain to functionally rescue a nonconducting, yet assembly and trafficking competent, long QT mutation located in the conserved COOH-terminal region of KCNE1.

scholarly journals Secondary structure analysis of the putative membrane-associated domains of the inward rectifier K+ channel ROMK1

1998 ◽  
Vol 335 (2) ◽  
pp. 375-380 ◽  
Author(s):  
Stephen P. BRAZIER ◽  
Bala. RAMESH ◽  
Parvez I. HARIS ◽  
David C. LEE ◽  
Surjit K. S. SRAI
Keyword(s):  
Gradient Centrifugation ◽  
Helical Structure ◽  
Structural Data ◽  
Cd Spectroscopy ◽  
Inward Rectifier ◽  
K Channel ◽  
Phospholipid Membranes ◽  
K Channels ◽  
Voltage Gated ◽  
Secondary Structure Analysis

The inward rectifier K+ channels contain two putative membrane-spanning domains per subunit (M1, M2) and a ‘pore ’ (P) region, which is similar to the H5 domain of voltage-gated K+ channels. Here we have used Fourier transform infrared (FTIR) and CD spectroscopy to analyse the secondary structures of synthetic peptides corresponding to the M1, M2 and P regions of ROMK1 in aqueous solution, in organic solvents and in phospholipid membranes. A previous CD study was unable to provide any structural data on a similar P peptide [Ben-Efraim and Shai (1997) Biophys. J. 72, 85–96]. However, our FTIR and CD spectroscopic analyses indicate that this peptide adopts an α-helical structure when reconstituted into dimyristoyl phosphatidylcholine vesicles and lysophosphatidyl choline (LPC) micelles as well as in trifluoroethanol (TFE) solvent. This result is in good agreement with a previous study on a peptide corresponding to the pore domain of a voltage-gated K+ channel [Haris, Ramesh, Sansom, Kerr, Srai and Chapman (1994) Protein Eng. 7, 255–262]. FTIR spectra of the M1 peptide in LPC micelles displayed a strong absorbance characteristic of an intermolecular β-sheet structure, suggesting aggregation of the M1 peptide. Sucrose gradient centrifugation was used to separate aggregated peptide from peptide incorporated into micelles in an unaggregated manner; subsequent analysis by FTIR suggested that the M1 peptide adopted an α-helical structure when incorporated into phospholipid membranes. FTIR and CD spectra of the M2 peptide in phospholipids and high concentrations of TFE suggest that this peptide adopts an α-helical structure. The structural data obtained in these experiments have been used to propose a model for the structure of the membrane-associated core (M1-P-M2) of the inward rectifier K+ channel protein.

scholarly journals Coupling of Voltage Sensing to Channel Opening Reflects Intrasubunit Interactions in Kv Channels

2004 ◽  
Vol 125 (1) ◽  
pp. 71-80 ◽  
Author(s):  
Alain J. Labro ◽  
Adam L. Raes ◽  
Dirk J. Snyders
Keyword(s):  
Voltage Dependence ◽  
Voltage Sensing ◽  
Α Subunit ◽  
K Channels ◽  
Voltage Gated ◽  
Kv Channels ◽  
Channel Opening ◽  
Subunit Stoichiometry ◽  
Voltage Dependent ◽  
Tetrameric Structure

Voltage-gated K+ channels play a central role in the modulation of excitability. In these channels, the voltage-dependent movement of the voltage sensor (primarily S4) is coupled to the (S6) gate that opens the permeation pathway. Because of the tetrameric structure, such coupling could occur within each subunit or between adjacent subunits. To discriminate between these possibilities, we analyzed various combinations of a S4 mutation (R401N) and a S6 mutation (P511G) in hKv1.5, incorporated into tandem constructs to constrain subunit stoichiometry. R401N shifted the voltage dependence of activation to negative potentials while P511G did the opposite. When both mutations were introduced in the same α-subunit of the tandem, the positive shift of P511G was compensated by the negative shift of R401N. With each mutation in a separate subunit of a tandem, this compensation did not occur. This suggests that for Kv channels, the coupling between voltage sensing and gating reflects primarily an intrasubunit interaction.

Inhibition of voltage-gated K+ channels mediates docosahexaenoic acid-stimulated insulin secretion in rat pancreatic β-cells

2020 ◽  
Vol 11 (10) ◽  
pp. 8893-8904
Author(s):  
Tao Bai ◽  
Huanhuan Yang ◽  
Hui Wang ◽  
Linping Zhi ◽  
Tao Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Docosahexaenoic Acid ◽  
Signaling Pathway ◽  
Vital Role ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Voltage Gated ◽  
Kv Channels

Kv channels play a vital role in DHA-augmented insulin secretion through GPR40/AC/cAMP/PLC signaling pathway in rat pancreatic β-cells.

scholarly journals Regulation of voltage-gated K+channels by glucose metabolism in pancreatic β-cells

FEBS Letters ◽  
2009 ◽  
Vol 583 (13) ◽  
pp. 2225-2230 ◽  
Author(s):  
Masashi Yoshida ◽  
Katsuya Dezaki ◽  
Shiho Yamato ◽  
Atsushi Aoki ◽  
Hitoshi Sugawara ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Voltage Gated

scholarly journals Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Nina E Ottosson ◽  
Xiongyu Wu ◽  
Andreas Nolting ◽  
Urban Karlsson ◽  
Per-Eric Lund ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Resin Acid ◽  
K Channels ◽  
Voltage Gated

scholarly journals Voltage‐gated K+ Channels as Potential Therapeutic Targets for Lung Adenocarcinoma Therapy

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
SO YEONG LEE ◽  
SOO HWA JANG ◽  
SUN YOUNG CHOI ◽  
PAN DONG RYU
Keyword(s):  
Lung Adenocarcinoma ◽  
Therapeutic Targets ◽  
K Channels ◽  
Voltage Gated
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