The road not taken: Evolution of tetrodotoxin resistance in the Sierra garter snake (<i>Thamnophis couchii</i>) by a path less travelled

Reimche, Jessica S.; Carlo, Robert E. del; Brodie, Edmund D.; McGlothlin, Joel W.; Schlauch, Karen; Pfrender, Michael E.; Leblanc, Normand; Feldman, Chris R.

doi:10.1111/mec.16538

Cited by 11 publications

(8 citation statements)

References 115 publications

(290 reference statements)

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“…Furthermore, evolutionary convergence is neither a prerequisite nor a sufficient condition for the evolution of toxin resistance either [45], as evidenced by the TTX-resistant species included in this study. In fact, while certain substitutions in the Na v 1.4 α subunit known to confer resistance to TTX are shared across garter snakes and pufferfishes, others are unique to each lineage [20,24,44]. Thus, the low convergence metrics we described in this study do not rule out a potential involvement of β subunits in conferring TTX resistance, pending experimental work.…”

Section: Discussionmentioning

confidence: 78%

“…However, the readily available Na v 1.4 α subunit sequences from a multitude of taxa (both TTX-sensitive and TTX-resistant) and the extensive research work conducted on this channel in relation to TTX binding offer a venue for in silico and/or in vitro studies of the interaction between TTX and the Na v 1.4 + β1 complex. With recent publications highlighting surprising results, such as novel substitutions conferring TTX resistance [44] and a lack of correlation between TTX resistance and polar contacts between the toxin and Na v 1.4 [45], this channel and subunit β1 would be the most reasonable candidates for experimental investigation of any β subunit involvement in TTX resistance.…”

Section: Discussionmentioning

confidence: 99%

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Sodium Channel β Subunits—An Additional Element in Animal Tetrodotoxin Resistance?

Seneci,

Mikheyev

2024

IJMS

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Tetrodotoxin (TTX) is a neurotoxic molecule used by many animals for defense and/or predation, as well as an important biomedical tool. Its ubiquity as a defensive agent has led to repeated independent evolution of tetrodotoxin resistance in animals. TTX binds to voltage-gated sodium channels (VGSC) consisting of α and β subunits. Virtually all studies investigating the mechanisms behind TTX resistance have focused on the α subunit of voltage-gated sodium channels, where tetrodotoxin binds. However, the possibility of β subunits also contributing to tetrodotoxin resistance was never explored, though these subunits act in concert. In this study, we present preliminary evidence suggesting a potential role of β subunits in the evolution of TTX resistance. We gathered mRNA sequences for all β subunit types found in vertebrates across 12 species (three TTX-resistant and nine TTX-sensitive) and tested for signatures of positive selection with a maximum likelihood approach. Our results revealed several sites experiencing positive selection in TTX-resistant taxa, though none were exclusive to those species in subunit β1, which forms a complex with the main physiological target of TTX (VGSC Nav1.4). While experimental data validating these findings would be necessary, this work suggests that deeper investigation into β subunits as potential players in tetrodotoxin resistance may be worthwhile.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Sodium Channel β Subunits—An Additional Element in Animal Tetrodotoxin Resistance?

Seneci,

Mikheyev

2024

IJMS

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“…This substitution was present in P. regilla that were sympatric and allopatric with Taricha . Amino acid changes in important regions of the Na V 1.4 protein do not always translate to a resistant phenotype or vice versa (e.g., see Abderemane-Ali et al, 2021; Reimche et al, 2022). Furthermore, the presence of this substitution in all P. regilla samples does not support our hypothesis that substitutions would only be found where P. regilla is exposed to TTX from sympatric Taricha (at least based on occurrence data from the last 50 yr).…”

Section: Discussionmentioning

confidence: 99%

Are Pacific Chorus Frogs (Pseudacris regilla) Resistant to Tetrodotoxin (TTX)? Characterizing Potential TTX Exposure and Resistance in an Ecological Associate of Pacific Newts (Taricha)

Montana

Ramírez‐Castañeda

Tarvin

2023

Journal of Herpetology

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Animals that frequently encounter toxins often develop mechanisms of toxin resistance over evolutionary time. Both predators that consume toxic prey and organisms in physical contact with a toxin in their environment may experience natural selection for resistance. Based on observations that Pacific Chorus Frogs (Pseudacris regilla) sometimes eat and mistakenly amplect tetrodotoxin (TTX)-defended Taricha newts, we predicted that P. regilla may possess TTX resistance. We compared amino acid sequences of domain IV of the muscle voltage-gated sodium channel gene SCN4A (NaV1.4) in populations of P. regilla that are sympatric and allopatric with Taricha. We identified a single substitution in NaV1.4 of P. regilla at a conserved site in the pore loop where TTX binds. Although the role of this site in TTX resistance has not been functionally assessed, both allopatric and sympatric P. regilla had this substitution, along with several other reptiles and amphibians, suggesting that it may be unrelated to TTX exposure from Taricha. Thus, there is no conclusive evidence that P. regilla possesses TTX resistance encoded by amino acid substitutions in this domain. California occurrence data from the last 50 yr indicate that Taricha activity peaks in January while the activity of P. regilla peaks in April, with times where the species may come into contact. However, P. regilla may not be exposed to levels of TTX from Taricha high enough to select for mutations in NaV1.4. Other unidentified mechanisms of TTX resistance could be present in P. regilla and other species sympatric with toxic newts.

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“…The copyright holder for this preprint this version posted December 11, 2023. ; https://doi.org/10.1101/2023.12.08.570760 doi: bioRxiv preprint confined to only those ecological communities or abiotic environments that can support the costly phenotypes those genotypes produce. Indeed, these TTX-resistant sodium channel genotypes are highly localized and only appear in certain "hotspots" rather than broadly distributed across the landscape as are toxin-sensitive animals 18,20,21,46,80 .…”

Section: Discussionmentioning

confidence: 99%

Coevolution with toxic prey produces functional trade-offs in sodium channels of predatory snakes

del Carlo,

Reimche,

Moniz

et al. 2023

Preprint

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Seemingly unrelated traits often share the same underlying molecular mechanisms, potentially generating a pleiotropic relationship whereby selection shaping one trait can simultaneously compromise another. While such functional trade-offs are expected to influence evolutionary outcomes, their actual relevance in nature is masked by obscure links between genotype, phenotype, and fitness. Here, we describe functional trade-offs that likely govern a key adaptation and coevolutionary dynamics in a predator-prey system. Several garter snake (Thamnophisspp.) populations have evolved resistance to tetrodotoxin (TTX), a potent chemical defense in their prey, toxic newts (Tarichaspp.). Snakes achieve TTX resistance through mutations occurring at toxin-binding sites in the pore of snake skeletal muscle voltage-gated sodium channels (NaV1.4). We hypothesized that these mutations impair basic NaVfunctions, producing molecular trade-offs that should ultimately scale up to compromised organismal performance. We investigate biophysical costs in two snake species with unique and independently evolved mutations that confer TTX resistance. We show electrophysiological evidence that skeletal muscle sodium channels encoded by toxin-resistant alleles are functionally compromised. Furthermore, skeletal muscles from snakes with resistance genotypes exhibit reduced mechanical performance. Lastly, modeling the molecular stability of these sodium channel variants partially explains the electrophysiological and muscle impairments. Ultimately, adaptive genetic changes favoring toxin resistance appear to negatively impact sodium channel function, skeletal muscle strength, and organismal performance. These functional trade-offs at the cellular and organ levels appear to underpin locomotor deficits observed in resistant snakes and may explain variation in the population-level success of toxin-resistant alleles across the landscape, ultimately shaping the trajectory of snake-newt coevolution.

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The road not taken: Evolution of tetrodotoxin resistance in the Sierra garter snake (Thamnophis couchii) by a path less travelled

Cited by 11 publications

References 115 publications

Sodium Channel β Subunits—An Additional Element in Animal Tetrodotoxin Resistance?

Sodium Channel β Subunits—An Additional Element in Animal Tetrodotoxin Resistance?

Are Pacific Chorus Frogs (Pseudacris regilla) Resistant to Tetrodotoxin (TTX)? Characterizing Potential TTX Exposure and Resistance in an Ecological Associate of Pacific Newts (Taricha)

Coevolution with toxic prey produces functional trade-offs in sodium channels of predatory snakes

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