Rapid toxin sequestration modifies poison frog physiology

O’Connell, Lauren A.; O’Connell, Jeremy D.; Paulo, João A.; Trauger, Sunia A.; Gygi, Steven P.; Murray, Andrew W.

doi:10.1242/jeb.230342

Cited by 26 publications

(35 citation statements)

References 45 publications

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“…It is possible that the ability to convert PTX 251D into aPTX 267A or sequester aPTX 267A to the skin has only been acquired in specific poison frog populations or species. The accumulation of both DHQ and PTX 251D in the liver, intestines, and skin, indicates that these tissues play an important role in the sequestration of alkaloids and echoes previous controlled feeding study results where frogs were only fed DHQ [14]. The liver and intestines are also important sites of alkaloid metabolism in mammals due to high levels of Cytochrome P450s [43][44][45].…”

Section: Plos Onesupporting

confidence: 79%

Molecular physiology of pumiliotoxin sequestration in a poison frog

Alvarez-Buylla¹,

Payne²,

Vidoudez³

et al. 2022

PLoS ONE

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Poison frogs bioaccumulate alkaloids for chemical defense from their arthropod diet. Although many alkaloids are accumulated without modification, some poison frog species can metabolize pumiliotoxin (PTX 251D) into the more potent allopumiliotoxin (aPTX 267A). Despite extensive research characterizing the chemical arsenal of poison frogs, the physiological mechanisms involved in the sequestration and metabolism of individual alkaloids remain unclear. We first performed a feeding experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if this species can metabolize PTX 251D into aPTX 267A and what gene expression changes are associated with PTX 251D exposure in the intestines, liver, and skin. We found that D. tinctorius can metabolize PTX 251D into aPTX 267A, and that PTX 251D exposure changed the expression level of genes involved in immune system function and small molecule metabolism and transport. To better understand the functional significance of these changes in gene expression, we then conducted a series of high-throughput screens to determine the molecular targets of PTX 251D and identify potential proteins responsible for metabolism of PTX 251D into aPTX 267A. Although screens of PTX 251D binding human voltage-gated ion channels and G-protein coupled receptors were inconclusive, we identified human CYP2D6 as a rapid metabolizer of PTX 251D in a cytochrome P450 screen. Furthermore, a CYP2D6-like gene had increased expression in the intestines of animals fed PTX, suggesting this protein may be involved in PTX metabolism. These results show that individual alkaloids can modify gene expression across tissues, including genes involved in alkaloid metabolism. More broadly, this work suggests that specific alkaloid classes in wild diets may induce physiological changes for targeted accumulation and metabolism.

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Section: Plos Onesupporting

confidence: 79%

Molecular physiology of pumiliotoxin sequestration in a poison frog

Alvarez-Buylla¹,

Payne²,

Vidoudez³

et al. 2022

PLoS ONE

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“…7 ). Together these observations suggest that poison frogs have a means to prevent BTX and STX engaging the target Na V s. It is notable that other frogs resist STX poisoning ( Prinzmetal et al, 1932 ; Kao and Fuhrman, 1967 ; Mahar et al, 1991 ), and it is thought that the soluble STX-binding protein Sxph ( Mahar et al, 1991 ; Arbuckle et al, 2017 ; Yen et al, 2019 ) acts as a toxin sponge to sequester and neutralize the lethal effects of this and possibly other neurotoxins ( Mahar et al, 1991 ; Llewellyn et al, 1997 ; Arbuckle et al, 2017 ; Almabruk et al, 2018 ; Caty et al, 2019 ; O’Connell et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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

Abderemane-Ali

Rossen

Kobiela

et al. 2021

Journal of General Physiology

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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.

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“…Lab feeding experiments have found that alkaloids accumulate primarily on the skin, although detectable quantities are also found in the liver and intestines [14]. This accumulation can occur within a few days [15,16], and is associated with changes in gene expression and protein abundance across tissues [15,16]. However, previous analyses of gene expression have been limited to comparing frogs with alkaloids to those without alkaloids.…”

Section: Introductionmentioning

confidence: 99%

“…However, previous analyses of gene expression have been limited to comparing frogs with alkaloids to those without alkaloids. [15-17], leaving a major gap in our understanding of how frog physiology changes in response to specific alkaloids rather than overall toxicity. Filling this knowledge gap is important because poison frogs carry many different alkaloid classes, each of which could potentially induce specific changes in physiology.…”

Section: Introductionmentioning

confidence: 99%

Molecular physiology of pumiliotoxin sequestration in a poison frog

Alvarez-Buylla

Payne

Vidoudez

et al. 2020

Preprint

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Poison frogs bioaccumulate alkaloids for chemical defense from their arthropod diet. These small molecules are sequestered from their gastrointestinal tract and transported to the skin for storage. Although many alkaloids are accumulated without modification, some poison frog species can metabolize pumiliotoxin (PTX 251D) into the more potent allopumiliotoxin (aPTX 267A). Despite extensive research characterizing the chemical arsenal of poison frogs, the physiological mechanisms involved in the sequestration and metabolism of individual alkaloids is unknown. We performed a feeding experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if this species can metabolize PTX 251D into aPTX 267A and what gene expression changes are associated with PTX 251D exposure in the intestines, liver, and skin. We found that D. tinctorius can metabolize PTX 251D into aPTX 267A, and that PTX 251D exposure changed the expression of genes involved in immune system function and small molecule metabolism and transport. These results show that individual alkaloids can modify gene expression across poison frog tissues and suggest that different alkaloid classes in wild diets may induce specific physiological changes for accumulation and metabolism.

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Rapid toxin sequestration modifies poison frog physiology

Cited by 26 publications

References 45 publications

Molecular physiology of pumiliotoxin sequestration in a poison frog

Molecular physiology of pumiliotoxin sequestration in a poison frog

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

Molecular physiology of pumiliotoxin sequestration in a poison frog

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