scholarly journals Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins

2021 ◽  
Vol 153 (9) ◽  
Author(s):  
Fayal Abderemane-Ali ◽  
Nathan D. Rossen ◽  
Megan E. Kobiela ◽  
Robert A. Craig ◽  
Catherine E. Garrison ◽  
...  
Keyword(s):  
Ion Channel ◽  
Sodium Channel ◽  
Small Molecule ◽  
Resistance Mechanism ◽  
Poison Frog ◽  
Poison Frogs ◽  
Toxin Resistance ◽  
Voltage Gated ◽  
Primary Driver ◽  
Toxin Sequestration

Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX “toxin sponge” protein saxiphilin is able to protect and rescue NaVs from block by STX. Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 N→T mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins.

scholarly journals Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs

2020 ◽  
Author(s):  
Fayal Abderemane-Ali ◽  
Nathan D. Rossen ◽  
Megan E. Kobiela ◽  
Robert A. Craig ◽  
Catherine E. Garrison ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Small Molecule ◽  
Resistance Mechanism ◽  
Resistance Mutations ◽  
Poison Frog ◽  
Poison Frogs ◽  
Toxin Resistance ◽  
Voltage Gated ◽  
Channel Function ◽  
Toxin Sequestration

AbstractPoisonous organisms carry small molecule toxins that alter voltage-gated sodium channel (Na✓) function. Among these, batrachotoxin (BTX) from Pitohui toxic birds and Phyllobates poison frogs, stands out because of its lethality and unusual effects on Nav function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a Nav DIVS6 pore-forming helix N→T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog Navs, incurs a strong cost that compromises channel function, and fails to produce BTX-resistant channels when tested in the context of poison frog Navs. We further show that captive-raised poison frogs are BTX resistant, even though they bear BTX-sensitive Navs. Hence, our data refute the hypothesis that BTX autoresistance is rooted in Nav mutations and instead suggest that more generalizable mechanisms such as toxin sequestration act to protect BTX-bearing species from autointoxication.

scholarly journals IDENTIFICATION OF THE kdr MUTATIONS IN VGSC GENE OF THE DENGUE MOSQUITOES AEDES ALBOPICTUS COLLECTED FROM HANOI AND HAIPHONG

2018 ◽  
Vol 16 (2) ◽  
pp. 273-278
Author(s):  
Nguyen Thi Kim Lien ◽  
Nguyen Thu Hien ◽  
Nguyen Huy Hoang ◽  
Nguyen Thi Hong Ngoc ◽  
Nguyen Thi Huong Binh
Keyword(s):  
Sodium Channel ◽  
Aedes Albopictus ◽  
Novel Mutation ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Resistance Mutations ◽  
Well Control ◽  
Voltage Gated ◽  
Activity Of Enzymes ◽  
Dengue Epidemic

Vietnam is one of the countries that is affected by dengue fever in Southeast Asia. The dengue epidemic is becoming increasingly more complex so it is necessary to have a well control to vectors in order to limit the spread of the disease. The Aedes albopictus mosquito is determined as one of the two major vectors that transmitted the dengue. Recent research shows that A. albopictus is present in some parts of Hanoi and Haiphong. In order to control the vector as well as the disease, it is necessary to understand the level of resistance and the resistance mechanism of the vector. Two important resistance mechanisms of insect were known as the mutations in the target protein of the insecticides and enhancing the activity of enzymes that participate in the resolution of the insecticides. In this study, the mosquito samples were collected from Hanoi and Haiphong to identify the level of resistance and detect the knock down resistance mutations in voltage gated sodium channel (VGSC) in membrane of nervecell of mosquito. The results of insecticide susceptibility test showed that A. albopictus in Hanoi and Haiphong were still sensitive to organophosphate but resistant to DDT, carbamate and pyrethroid. Ser989Pro, Ile1011Met, Val1016Gly and Phe1534Cys mutations were not deteced in A. albopictus in Hanoi and Haiphong. However, we detected a novel mutation Tyr986His in VGSC protein.

scholarly journals Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs

2019 ◽  
Vol 37 (2) ◽  
pp. 607-607
Author(s):  
Rebecca D Tarvin ◽  
Juan C Santos ◽  
Lauren A O'Connell ◽  
Harold H Zakon ◽  
David C Cannatella
Keyword(s):  
Sodium Channel ◽  
Poison Frogs ◽  
Toxin Resistance ◽  
Multiple Origins

scholarly journals Oleamide in Ipomoea and Dillenia species and inflammatory activity investigated through ion channel inhibition

2020 ◽  
Vol 21 ◽  
Author(s):  
Unchaleeporn Ameamsri ◽  
Arunrat Chaveerach ◽  
Runglawan Sudmoon ◽  
Tawatchai Tanee ◽  
Steve Peigneur ◽  
...  
Keyword(s):  
Ion Channel ◽  
Potassium Channel ◽  
Sodium Channel ◽  
Ex Vivo ◽  
Inflammatory Activity ◽  
Leaf Extracts ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Channel Inhibition ◽  
Anti Inflammatory

Background: Oleamide is an essential substance for human health. So, the plants with high oleamide content are great sources for health care products. Objective: This study is conducted to investigate the quality of oleamide in plants and test the bioactivity in the selected two studied species. Methods: The three Ipomoea and five Dillenia species including Ipomoea alba, Ipomoea aquatica and Ipomoea pes-caprae, and Dillenia indica, Dillenia obovata, Dillenia ovata, Dillenia parviflora and Dillenia pentagyna were investigated for the quantity of oleamide by high-performance liquid chromatography. The biological activity test was conducted on the powder formulation of the chosen plants, Dillenia ovata and Dillenia parviflora at a ratio of 30:70, for anti-inflammatory activity ex vivo on a panel of molecular targets through ion channel inhibition including voltage-gated sodium channel, voltage-gated potassium channel, and the cardiac ion as human ether-a-go-go related gene. Results: The results showed that the leaf extracts of I. aquatica and D. ovata gave the highest and subsequent oleamide quantity following 7.52 and 5.17 mg/g. Out of the Dillenia formulation which contained various compounds, oleamide showed the highest percentages of inhibition at 8.0-20.0%, and 6.2-14.2% in voltage-gated sodium channel, and voltage-gated potassium channel which had slightly lower values than the oleamide standard, and no effect as 0.0% value inhibition in the cardiac ion channel. Conclusion: The Dillenia formulation exhibits anti-inflammatory activity without affecting the heart. Accordingly, the three studied Ipomoea and three studied Dillenia species may be used for the same activity as a single component or formulation with effective solvent for disease treatments.

scholarly journals Molecular Insight into the Knockdown Resistance (kdr) in the Voltage Gated Sodium Channel (vgsc) Gene of the Main Dengue Vector, Aedes aegypti (Diptera: Culicidae) and the Discovery of Novel Regional Specific Point Mutation A1007G in Malaysia.

2021 ◽  
Author(s):  
Mas Azlin M. Akhir ◽  
Mustafa F. F. Wajidi ◽  
Sébastien Lavoué ◽  
Ghows Azzam ◽  
Izhan Shahrin Jaafar ◽  
...  
Keyword(s):  
Insecticide Resistance ◽  
Sodium Channel ◽  
Vector Control ◽  
Resistance Mechanism ◽  
Point Mutations ◽  
Voltage Gated Sodium Channel ◽  
Pyrethroid Insecticides ◽  
Voltage Gated ◽  
Control Programmes ◽  
Pirimiphos Methyl

Abstract Background: Characterization of the insecticide resistance mechanism imparts the society with the information on the evolutionary process involved in the adaptation of Aedes aegypti mosquito to environmental changes. Investigating the phenotypic status of the target mosquitoes, their resistance level as well as elucidating the genotypic profile provides information about the involvement of insecticide resistance mechanism, in terms of portraying the evolution of resistance in the field, to eventually managing vector control programmes. In this current study, we investigated the quantification responses for the phenotypic and genotypic resistance of Ae. aegypti population from different states in Malaysia. Methods: We tested insecticide susceptibility status of adult Ae. aegypti from populations of States of Penang, Selangor and Kelantan (Peninsular Malaysia) against 0.25% permethrin and 0.25% pirimiphos-methyl through WHO bioassay kit. Permethrin-resistant and permethrin susceptible samples were then genotyped for domains II and III in the voltage gated sodium channel (vgsc) gene using allele specific PCR (AS-PCR) for the presence of diagnostic single nucleotide mutations. AS-PCR results were then validated in sequencing these two domains to identify any possible additional point mutations. Results: Adult WHO bioassay revealed that populations of Ae. aegypti from these three states were highly resistant towards 0.25% permethrin and 0.25% pirimiphos-methyl. Genotyping results showed that three knockdown (kdr) mutations (i.e. S989P, V1016G and F1534C) were associated with pyrethroid resistance in these populations. We also report for the first time the presence of the A1007G mutation in Malaysian populations of Ae. aegypti.Conclusions: This study brings an insight on the occurrence and association of point mutations with insecticide resistance in Malaysian populations of Ae. aegypti. The results reveal the widespread of several kdr mutations in the field with the consequence to compromise the use of pyrethroid insecticides in vector control programmes. Knowledge on the distribution of target site resistance throughout Malaysia is vital to ensure the success of the insecticide-based vector control programme.

scholarly journals Rapid toxin sequestration modifies poison frog physiology

2021 ◽  
pp. jeb.230342
Author(s):  
Lauren A. O'Connell ◽  
Jeremy D. O'Connell ◽  
Joao A. Paulo ◽  
Sunia A. Trauger ◽  
Steven P. Gygi ◽  
...  
Keyword(s):  
Small Molecule ◽  
Chemical Defenses ◽  
Protein Abundance ◽  
Poison Frog ◽  
Poison Frogs ◽  
Toxin Binding ◽  
Physiological Adaptations ◽  
Molecule Transport ◽  
Protein Classes ◽  
Small Molecule Transport

Poison frogs sequester chemical defenses from their diet of leaf litter arthropods for defense against predation. Little is known about the physiological adaptations that confer this unusual bioaccumulation ability. We conducted an alkaloid-feeding experiment with the Diablito poison frog (Oophaga sylvatica) to determine how quickly alkaloids are accumulated and how toxins modify frog physiology using quantitative proteomics. Diablito frogs rapidly accumulated the alkaloid decahydroquinoline within four days, and dietary alkaloid exposure altered protein abundance in the intestines, liver, and skin. Many proteins that increased in abundance with decahydroquinoline accumulation are plasma glycoproteins, including the complement system and the toxin-binding protein saxiphilin. Other protein classes that change in abundance with decahydroquinoline accumulation are membrane proteins involved in small molecule transport and metabolism. Overall, this work shows poison frogs can rapidly accumulate alkaloids, which alter carrier protein abundance, initiate an immune response, and alter small molecule transport and metabolism dynamics across tissues.

Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs

2016 ◽  
Vol 33 (4) ◽  
pp. 1068-1080 ◽  
Author(s):  
Rebecca D Tarvin ◽  
Juan C Santos ◽  
Lauren A O'Connell ◽  
Harold H Zakon ◽  
David C Cannatella
Keyword(s):  
Amino Acid ◽  
Sodium Channel ◽  
Chemical Defense ◽  
Protein Docking ◽  
Genetic Changes ◽  
Poison Frogs ◽  
Toxin Resistance ◽  
Multiple Origins ◽  
Inner Pore

Abstract Complex phenotypes typically have a correspondingly multifaceted genetic component. However, the genotype–phenotype association between chemical defense and resistance is often simple: genetic changes in the binding site of a toxin alter how it affects its target. Some toxic organisms, such as poison frogs (Anura: Dendrobatidae), have defensive alkaloids that disrupt the function of ion channels, proteins that are crucial for nerve and muscle activity. Using protein-docking models, we predict that three major classes of poison frog alkaloids (histrionicotoxins, pumiliotoxins, and batrachotoxins) bind to similar sites in the highly conserved inner pore of the muscle voltage-gated sodium channel, Nav1.4. We predict that poison frogs are somewhat resistant to these compounds because they have six types of amino acid replacements in the Nav1.4 inner pore that are absent in all other frogs except for a distantly related alkaloid-defended frog from Madagascar, Mantella aurantiaca. Protein-docking models and comparative phylogenetics support the role of these replacements in alkaloid resistance. Taking into account the four independent origins of chemical defense in Dendrobatidae, phylogenetic patterns of the amino acid replacements suggest that 1) alkaloid resistance in Nav1.4 evolved independently at least five times in these frogs, 2) variation in resistance-conferring replacements is likely a result of differences in alkaloid exposure across species, and 3) functional constraint shapes the evolution of the Nav1.4 inner pore. Our study is the first to demonstrate the genetic basis of autoresistance in frogs with alkaloid defenses.

scholarly journals Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

2021 ◽  
Vol 12 ◽  
Author(s):  
Ibitayo Abigail Ademuwagun ◽  
Solomon Oladapo Rotimi ◽  
Steffen Syrbe ◽  
Yvonne Ukamaka Ajamma ◽  
Ezekiel Adebiyi
Keyword(s):  
Ion Channel ◽  
Sodium Channel ◽  
Sodium Channels ◽  
De Novo ◽  
Single Gene ◽  
Voltage Gated ◽  
Functional Studies ◽  
Voltage Gated Sodium Channels ◽  
Genomic Studies ◽  
The Brain

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

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