Agatoxin

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Kurt M. Howse - One of the best experts on this subject based on the ideXlab platform.

  • ω-Agatoxin IVA blocks spinal morphine/clonidine antinociceptive synergism
    European journal of pharmacology, 1996
    Co-Authors: Sandra C. Roerig, Kurt M. Howse
    Abstract:

    Abstract Involvement of P-type voltage-dependent Ca2+ channels in spinal morphine- or clonidine-induced antinociception and in the synergistic interaction between morphine and clonidine was examined in the present studies. Coadministration of the selective P-type antagonist, ω-Agatoxin IVA (25 ng) intrathecally (i.t.) to mice along with morphine or clonidine enhanced the tail flick antinociception of each agonist 5–6-fold. The greater-than-additive (synergistic) interaction that occurred when morphine and clonidine were coadministered i.t. decreased to an additive interaction in the presence of ω-Agatoxin IVA. In mice pretreated with pertussis toxin (10 ng) to inactivate G proteins, ω-Agatoxin IVA did not alter the morphine/clonidine synergism. Surprisingly, ω-Agatoxin IVA reversed the additive morphine/clonidine interaction that occurs in morphine-tolerant mice back to synergism. These results suggest that functional P-type Ca2+ channels play an essential role in the antinociceptive synergism between spinal morphine and clonidine.

  • ω Agatoxin iva blocks spinal morphine clonidine antinociceptive synergism
    European Journal of Pharmacology, 1996
    Co-Authors: Sandra C. Roerig, Kurt M. Howse
    Abstract:

    Abstract Involvement of P-type voltage-dependent Ca2+ channels in spinal morphine- or clonidine-induced antinociception and in the synergistic interaction between morphine and clonidine was examined in the present studies. Coadministration of the selective P-type antagonist, ω-Agatoxin IVA (25 ng) intrathecally (i.t.) to mice along with morphine or clonidine enhanced the tail flick antinociception of each agonist 5–6-fold. The greater-than-additive (synergistic) interaction that occurred when morphine and clonidine were coadministered i.t. decreased to an additive interaction in the presence of ω-Agatoxin IVA. In mice pretreated with pertussis toxin (10 ng) to inactivate G proteins, ω-Agatoxin IVA did not alter the morphine/clonidine synergism. Surprisingly, ω-Agatoxin IVA reversed the additive morphine/clonidine interaction that occurs in morphine-tolerant mice back to synergism. These results suggest that functional P-type Ca2+ channels play an essential role in the antinociceptive synergism between spinal morphine and clonidine.

Michael E. Adams - One of the best experts on this subject based on the ideXlab platform.

  • Heterodimeric
    2013
    Co-Authors: Brian T. Chait, Michael E. Adams, John P. Hunspergers, Baldomero M. Oliveras, David R. Hillyard
    Abstract:

    We report the first molecular characterization of a precursor sequence for a small, Ca2+ channel blocking, peptide spider toxin, w-Agatoxin IA. By integrating information generated from a molecular genetic approach using Agatoxin cDNAs with data provided from mass spectrometry of the mature toxin, we were able to deduce the likely mechanisms by which the toxin precursor peptide is processed to its mature heterodimeric form. A particularly interesting feature of the prepropeptide is the occurrence of two glutamate-rich sequences interposed between the signal sequences, the major peptide toxin, and the minor toxin peptide. Excision of the more distal glutamate-rich region appears to be signaled by flanking arginine residues but likely occurs only after a disulfide linkage has formed betwee

  • Agatoxins: ion channel specific toxins from the American funnel web spider, Agelenopsis aperta.
    Toxicon : official journal of the International Society on Toxinology, 2004
    Co-Authors: Michael E. Adams
    Abstract:

    Agatoxins from Agelenopsis aperta venom target three classes of ion channels, including transmitter-activated cation channels, voltage-activated sodium channels, and voltage-activated calcium channels. The α-Agatoxins are non-competitive, use-dependent antagonists of glutamate receptor channels, and produce rapid but reversible paralysis in insect prey. Their actions are facilitated by the μ-Agatoxins, which shift voltage-dependent activation of neuronal sodium channels to more negative potentials, causing spontaneous transmitter release and repetitive action potentials. The ω-Agatoxins target neuronal calcium channels, modifying their properties in distinct ways, either through gating modification (ω-Aga-IVA) or by reduction of unitary current (ω-Aga-IIIA). The α-Agatoxins and ω-Agatoxins modify both insect and vertebrate ion channels, while the μ-Agatoxins are selective for insect channels. Agatoxins have been used as selective pharmacological probes for characterization of ion channels in the brain and heart, and have been evaluated as candidate biopesticides.

  • Three-dimensional structure analysis of mu-Agatoxins: further evidence for common motifs among neurotoxins with diverse ion channel specificities.
    Biochemistry, 1996
    Co-Authors: Diana O. Omecinsky, Michael E. Adams, Katherine E. Holub, Michael D. Reily
    Abstract:

    We report the solution structure of mu-Agatoxin-I (mu-Aga-I) and model structures of the closely related mu-Agatoxin-IV (mu-Aga-IV) which were isolated from venom of the American funnel web spider, Agelenopsis aperta. These toxins, which modify the kinetics of neuronal voltage-activated sodium channels in insects, are C-terminally amidated peptides composed to 36 amino acids, including four internal disulfide bonds. The structure of mu-Aga-I was determined by NMR and distance geometry/molecular dynamics calculations. Structural calculations were carried out using 256 interresidue NOE-derived distance restraints and 25 angle restraints obtained from vicinal coupling constants. The peptide contains eight cysteines involved in disulfide bonds, the pairings of which were uncertain and had to be determined from preliminary structure calculations. The toxin has an average rmsd of 0.89 A for the backbone atoms among 38 converged conformers. The structure consists of a well-defined triple-stranded beta-sheet involving residues 7-9, 20-24, and 30-34 and four tight turns. A homologous peptide, mu-Aga-IV, exhibited two distinct and equally populated conformations in solution, which complicated spectral analysis. Analysis of sequential NOE's confirmed that the conformers arose from cis and trans peptide bonds involving a proline at position 15. Models were developed for both conformers based on the mu-Aga-I structure. Our structural data show that the mu-Agatoxins, although specific modifiers of sodium channels, share common secondary and tertiary structural motifs with phylogenetically diverse peptide toxins targeting a variety of channel types. The mu-Agatoxins add voltage-sensitive sodium channel activity to a growing list of neurotoxic effects elicited by peptide toxins which share the same global fold yet differ in their animal origin and ion channel selectivity.

  • Type III omega-Agatoxins: a family of probes for similar binding sites on L- and N-type calcium channels.
    Biochemistry, 1994
    Co-Authors: Eric A. Ertel, Michael E. Adams, Vivien A. Warren, Patrick R. Griffin, Charles J. Cohen, Mchardy M. Smith
    Abstract:

    The peptide omega-Agatoxin-IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis aperta is the only known agent that blocks L-type and N-type Ca channels with equal high potency (IC50 < or = 1 nM). From the same venom, we have purified and sequenced a family of peptides which are homologous to omega-Aga-IIIA but vary over 100-fold in their relative affinity for L-type versus N-type Ca channels. One of these, omega-Aga-IIIB, is 76 amino acids long and identical to omega-Aga-IIIA in 66 positions. We identified two other similar peptides, omega-Aga-IIIC and omega-Aga-IIID, as well as one single amino acid variant of omega-Aga-IIIA and two of omega-Aga-IIIB. The type III omega-Agatoxins exhibit similar but distinct activities on voltage-gated Ca channels. omega-Aga-IIIA, omega-Aga-IIIB, and omega-Aga-IIID are nearly indistinguishable in their actions at the insect neuromuscular junction (no effect at 0.1 microM), on atrial T-type Ca channels (no effect at 0.5 microM), and in two assays for synaptosomal Ca channels: they are nearly equipotent inhibitors of 125I-omega-conotoxin GVIA binding to rat brain synaptic membranes (IC50 = 0.17-0.33 nM) and blockers of the K(+)-induced 45Ca2+ influx into chick brain synaptosomes (omega-Aga-IIIB, 1.2 nM; omega-Aga-IIIA, 2.4 nM). In contrast, omega-Aga-IIIA is a better blocker of locust Ca channels (IC50 approximately 10-50 nM) than is omega-Aga-IIIB. Finally, although omega-Aga-IIIA, omega-Aga-IIIB, and omega-Aga-IIID all block atrial L-type Ca channels, omega-Aga-IIIA is over 100-fold more potent. Thus, although type III omega-Agatoxins appear to recognize a binding site common to L- and N-type Ca channels, omega-Aga-IIIB and omega-Aga-IIID identify differences between the two channels.

  • Autoradiographic localization of the binding of calcium channel antagonist, [125I]ω-Agatoxin IIIA, in rat brain
    Brain research, 1992
    Co-Authors: J.m. Mcintosh, Baldomero M. Olivera, Michael E. Adams, Francis Filloux
    Abstract:

    The calcium channel antagonists omega-Agatoxin IIIA (omega-Aga-IIIA) and omega-conotoxin GVIA (omega-CgTx) were radioiodinated and used to locate binding sites in the rat brain by receptor autoradiography. While patterns of regional binding to sagittal sections of rat brain were generally similar for the 2 toxins, notable differences in the cerebellum and hippocampus were observed. Specific [125I]omega-Aga-IIIA binding was greatest in the granule cell layers of the cerebellum and of the dentate gyrus. In contrast, binding of [125I]omega-CgTx was most intense in the molecular layers of these structures. Less than one-third of [125I]omega-Aga-IIIA binding in rat brain slices was inhibited by pre-exposure to 250 nM omega-CgTx, while 40 nM omega-Aga-IIIA virtually eliminated the binding of [125I]omega-CgTx under the same conditions. The P-type calcium channel antagonist omega-Aga-IVA blocked only a small fraction of [125I]omega-Aga-IIIA and [125I]omega-CgTx binding. These autoradiographic data are consistent with membrane binding experiments and indicate that the combined use of Agatoxins and conotoxins may be useful in the characterization of separate types of neuronal calcium channels.

Sandra C. Roerig - One of the best experts on this subject based on the ideXlab platform.

  • ω-Agatoxin IVA blocks spinal morphine/clonidine antinociceptive synergism
    European journal of pharmacology, 1996
    Co-Authors: Sandra C. Roerig, Kurt M. Howse
    Abstract:

    Abstract Involvement of P-type voltage-dependent Ca2+ channels in spinal morphine- or clonidine-induced antinociception and in the synergistic interaction between morphine and clonidine was examined in the present studies. Coadministration of the selective P-type antagonist, ω-Agatoxin IVA (25 ng) intrathecally (i.t.) to mice along with morphine or clonidine enhanced the tail flick antinociception of each agonist 5–6-fold. The greater-than-additive (synergistic) interaction that occurred when morphine and clonidine were coadministered i.t. decreased to an additive interaction in the presence of ω-Agatoxin IVA. In mice pretreated with pertussis toxin (10 ng) to inactivate G proteins, ω-Agatoxin IVA did not alter the morphine/clonidine synergism. Surprisingly, ω-Agatoxin IVA reversed the additive morphine/clonidine interaction that occurs in morphine-tolerant mice back to synergism. These results suggest that functional P-type Ca2+ channels play an essential role in the antinociceptive synergism between spinal morphine and clonidine.

  • ω Agatoxin iva blocks spinal morphine clonidine antinociceptive synergism
    European Journal of Pharmacology, 1996
    Co-Authors: Sandra C. Roerig, Kurt M. Howse
    Abstract:

    Abstract Involvement of P-type voltage-dependent Ca2+ channels in spinal morphine- or clonidine-induced antinociception and in the synergistic interaction between morphine and clonidine was examined in the present studies. Coadministration of the selective P-type antagonist, ω-Agatoxin IVA (25 ng) intrathecally (i.t.) to mice along with morphine or clonidine enhanced the tail flick antinociception of each agonist 5–6-fold. The greater-than-additive (synergistic) interaction that occurred when morphine and clonidine were coadministered i.t. decreased to an additive interaction in the presence of ω-Agatoxin IVA. In mice pretreated with pertussis toxin (10 ng) to inactivate G proteins, ω-Agatoxin IVA did not alter the morphine/clonidine synergism. Surprisingly, ω-Agatoxin IVA reversed the additive morphine/clonidine interaction that occurs in morphine-tolerant mice back to synergism. These results suggest that functional P-type Ca2+ channels play an essential role in the antinociceptive synergism between spinal morphine and clonidine.

Koichi Tan-no - One of the best experts on this subject based on the ideXlab platform.

  • Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel α1 subunits in the dorsal horn of spinal cord in mice
    Brain Research, 2004
    Co-Authors: Manabu Murakami, Osamu Nakagawasai, Takashi Suzuki, Izadi I Mobarakeh, Yumiko Sakurada, Astunobu Murata, Fumihiro Yamadera, Ichiro Miyoshi, Kazuhiko Yanai, Koichi Tan-no
    Abstract:

    To understand better which voltage-dependent calcium channels (VGCCs) are involved in nociceptive neurotransmission, we investigated the pharmacological properties and distribution of VGCCs in the mouse spinal cord. A behavioral assay revealed that intrathecal injections of ω-Agatoxin TK, ω-Agatoxin IVA, ω-conotoxin GVIA, and SNX-482, which block P/Q-, P/Q-, N-, and R-type calcium channels, respectively, produced analgesic effects, while an L-type channel blocker had no such effect. An electrophysiological study demonstrated the presence of various types of VGCCs within dorsal root ganglion (DRG) neurons. Immunohistochemistry revealed distinct localization of P/Q-, N-, L-, and R-type calcium channel subunits to the dorsal horn of the spinal cord. The results of this study revealed the localization and functions of several calcium channels that are involved in nociceptive neurotransmission within the dorsal horn of the mouse spinal cord.

  • Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel alpha 1 subunits in the dorsal horn of spinal cord in mice.
    Brain Research, 2004
    Co-Authors: Manabu Murakami, Osamu Nakagawasai, Takashi Suzuki, Izadi I Mobarakeh, Yumiko Sakurada, Astunobu Murata, Fumihiro Yamadera, Ichiro Miyoshi, Kazuhiko Yanai, Koichi Tan-no
    Abstract:

    To understand better which voltage-dependent calcium channels (VGCCs) are involved in nociceptive neurotransmission, we investigated the pharmacological properties and distribution of VGCCs in the mouse spinal cord. A behavioral assay revealed that intrathecal injections of omega-Agatoxin TK, omega-Agatoxin IVA, omega-conotoxin GVIA, and SNX-482, which block P/Q-, P/Q-, N-, and R-type calcium channels, respectively, produced analgesic effects, while an L-type channel blocker had no such effect. An electrophysiological study demonstrated the presence of various types of VGCCs within dorsal root ganglion (DRG) neurons. Immunohistochemistry revealed distinct localization of P/Q-, N-, L-, and R-type calcium channel subunits to the dorsal horn of the spinal cord. The results of this study revealed the localization and functions of several calcium channels that are involved in nociceptive neurotransmission within the dorsal horn of the mouse spinal cord.

Seung Yeol Nah - One of the best experts on this subject based on the ideXlab platform.

  • Effect of ginsenosides on voltage-dependent Ca2+ channel subtypes in bovine chromaffin cells
    Journal of ethnopharmacology, 2001
    Co-Authors: Seok Choi, Hack Seang Kim, Hye Whon Rhim, Seok Chang Kim, Se-yeon Jung, Cheon-ho Kim, Seung Yeol Nah
    Abstract:

    Abstract In previous reports we have shown that ginsenosides inhibit high threshold voltage-dependent Ca2+ channels in neuronal cells. However, these studies did not show whether ginsenosides-induced inhibition of Ca2+ currents discriminates among the various Ca2+ channel subtypes, although it is known that there are at least five different Ca2+ channel subtypes in neuronal cells. In this study we investigated the effect of ginsenosides on high threshold voltage-dependent Ca2+ channel subtypes using their selective Ca2+ channel blockers nimodipine (L-type), ω-conotoxin GVIA (N-type), or ω-Agatoxin IVA (P-type) in bovine chromaffin cells. We could observe that ginsenosides inhibited high threshold voltage-dependent Ca2+ currents in a dose-dependent manner. The IC50 was about 120 μg/ml. Nimodipine had no effect on ginsenosides response. However, the effect of ginsenosides on Ca2+ currents was reduced by ω-conotoxin GVIA, ω-Agatoxin IVA, and mixture of nimodipine, ω-conotoxin GVIA, and ω-Agatoxin IVA. These data suggest that ginsenosides are negatively coupled to three types of calcium channels in bovine chromaffin cell, including an ω-conotoxin GVIA-sensitive (N-type) channel, an ω-Agatoxin IVA-sensitive (P-type) channel and nimodipine/ω-conotoxin GVIA/ω-Agatoxin VIA-resistant (presumptive Q-type) channel. Thus, the selective regulation of voltage-dependent Ca2+ subtypes by ginsenosides in bovine chromaffin cell could be the cellular basis of antistress effects induced by ginseng.

  • Ginsenosides Inhibit N-, P-, and Q-types but not L-type of Ca2+ Channel in Bovine Chromaffin cells
    Journal of Ginseng Research, 2000
    Co-Authors: Seol Choi, Yeon Jung, Hyun Oh Kim, Hack Seang Kim, Hye Whon Rhim, Seok Chang Kim, Seung Yeol Nah
    Abstract:

    In previous reports we have shown that ginsenosides inhibit high threshold voltage-dependent channels in neuronal cells. However, these studies did not show whether ginsenosides-induced inhibition of currents discriminates among the various channel subtypes, although it is known that there are at least five different channel subtypes in neuronal cells. In this study we investigated the effect of ginsenosides on high threshold voltage-dependent channel subtypes using their selective channel blockers nimodipine (L-type), -conotoxin GVIA (N-type), or -Agatoxin IVA (P-type) in bovine chromaffin cells. We could observe that ginsenosides inhibited high threshold voltage-dependent currents in a dose-dependent manner. The / was about 120 g/ml. Nimodipine had no effect on ginsenosides response. However, the effect of ginsenosides on currents was reduced by -conotoxin GVIA, -Agatoxin IVA, and mixture of nimodipine, -contoxin GVIA, and -Agatoxin IVA. These data suggest that ginsenosides are negatively coupled to three types of calcium channels in bovine chromaffin cell, including an -conotoxin GVIA-sensitive (N-type) channel, an -Agatoxin IVA-sensitive (P-type) channel and nimodipine/-conotoxin GVIA/-Agatoxin IVA-resistant (presumptive Q-type) channel.Q-type) channel.