Synthesis and Biological Activity of Argiotoxin 636 and Analogues: Selective Antagonists for Ionotropic Glutamate Receptors

Nelson, Jared K.; Frølund, Sidsel; Tikhonov, Denis B.; Kristensen, Anders S.; Strømgaard, Kristian

doi:10.1002/anie.200805426

Cited by 33 publications

(40 citation statements)

References 27 publications

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“…The biosynthesis of phevamine A is controlled by the HrpL virulence regulator in P. syringae . Interestingly, phevamine A shares structural similarity with insect polyamine toxins: argiotoxin from the orb-weaver spider, and philanthotoxin from the Egyptian solitary wasp, both of which contain a polyamine and two amino acids, and are powerful neurotoxins that target ion channels ( 49 , 50 ). The structural similarity suggests related mechanisms, which will be the focus of future studies.…”

Section: Discussionmentioning

confidence: 99%

Phevamine A, a small molecule that suppresses plant immune responses

O'Neill

Mucyn

Patteson

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceBacterial pathogens cause plant diseases that threaten the global food supply. To control diseases, it is important to understand how pathogenic bacteria evade plant defense and promote infection. We identify from the phytopathogen Pseudomonas syringae a small-molecule virulence factor—phevamine A. Both the chemical structure and mode of action of phevamine A are different from known bacterial phytotoxins. Phevamine A promotes bacterial growth by suppressing plant immune responses, including both early (the generation of reactive oxygen species) and late (the deposition of cell wall reinforcing callose in leaves and leaf cell death) markers. This work uncovers a widely distributed, small-molecule virulence factor and shows the power of a multidisciplinary approach to identify small molecules important for plant infection.

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Section: Discussionmentioning

confidence: 99%

Phevamine A, a small molecule that suppresses plant immune responses

O'Neill

Mucyn

Patteson

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The axial binding mode was previously proposed for potent AMPAR channel blockers (Tikhonov, ; Nelson et al ., ). For compounds such as philanthotoxins and IEM‐1460, this binding mode dominates because their length allows them to interact simultaneously with the selectivity filter (Q/R site) and the deeply located Gly ring (Tikhonov, ).…”

Section: Resultsmentioning

confidence: 97%

Non‐classical mechanism of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor channel block by fluoxetine

Barygin

Komarova

Tikhonova

et al. 2014

Eur J of Neuroscience

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Antidepressants have many targets in the central nervous system. A growing body of data demonstrates the influence of antidepressants on glutamatergic neurotransmission. In the present work, we studied the inhibition of native Ca(2+)-permeable and Ca(2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca(2+)-impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC50 value for the inhibition of Ca(2+)-permeable AMPA receptors in giant striatal interneurons was 43 ± 7 μM. The inhibition of Ca(2+)-permeable AMPA receptors was voltage dependent, suggesting deep binding in the pore. However, the use dependence of fluoxetine action differed markedly from that of classical AMPA receptor open-channel blockers. Moreover, fluoxetine did not compete with other channel blockers. In contrast to fluoxetine, its membrane-impermeant quaternary analog demonstrated all of the features of channel inhibition typical for open-channel blockers. It is suggested that fluoxetine reaches the binding site through a hydrophobic access pathway. Such a mechanism of block is described for ligands of sodium and calcium channels, but was never found in AMPA receptors. Molecular modeling suggests binding of fluoxetine in the subunit interface; analogous binding was proposed for local anesthetics in closed sodium channels and for benzothiazepines in calcium channels.

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“…The ligand, an acylated polyamine, is thought to interact with the ion conduction pore of CP‐AMPARs where it halts ion flow (Nelson et al . ). Our method allows us to detect the CP‐AMPAR subtype in the milieu of other AMPARs expressed in neurons.…”

Section: Discussionmentioning

confidence: 97%

Ligand‐directed delivery of fluorophores to track native calcium‐permeable AMPA receptors in neuronal cultures

Combs-Bachmann

Johnson

Vytla

et al. 2015

Journal of Neurochemistry

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Subcellular trafficking of neuronal receptors is known to play a key role in synaptic development, homeostasis, and plasticity. We have developed a ligand-targeted and photo-cleavable probe for delivering a synthetic fluorophore to AMPA receptors natively expressed in neurons. After a receptor is bound to the ligand portion of the probe molecule, a proteinaceous nucleophile reacts with an electrophile on the probe, covalently bonding the two species. The ligand may then be removed by photolysis, returning the receptor to its non-liganded state while leaving intact the new covalent bond between the receptor and the fluorophore. This strategy was used to label polyamine-sensitive receptors, including calcium-permeable AMPA receptors, in live hippocampal neurons from rats. Here, we describe experiments where we examined specificity, competition, and concentration on labeling efficacy as well as quantified receptor trafficking. Pharmacological competition during the labeling step with either a competitive or noncompetitive glutamate receptor antagonist prevented the majority of labeling observed without a blocker. In other experiments, labeled receptors were observed to alter their locations and we were able to track and quantify their movements.

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Synthesis and Biological Activity of Argiotoxin 636 and Analogues: Selective Antagonists for Ionotropic Glutamate Receptors

Cited by 33 publications

References 27 publications

Phevamine A, a small molecule that suppresses plant immune responses

Phevamine A, a small molecule that suppresses plant immune responses

Non‐classical mechanism of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor channel block by fluoxetine

Ligand‐directed delivery of fluorophores to track native calcium‐permeable AMPA receptors in neuronal cultures

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