Molecular basis for the insensitivity of the Monarch (<i>Danaus plexippus</i>) to cardiac glycosides

Holzinger, F.; Frick, Christoph; Wink, Michael

doi:10.1016/0014-5793(92)81530-y

Cited by 122 publications

(95 citation statements)

References 18 publications

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“…Interestingly, other species besides rodents have a cardiac glycoside-resistant ␣1 isoform. These include some Bufo species (55) and Monarch butterf lies (56). This resistance could have developed for a number of reasons.…”

Section: Discussionmentioning

confidence: 99%

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Dostanic-Larson

Huysse

Lorenz

et al. 2005

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

175

190

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The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo. Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase ␣2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant ␣2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the ␣1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant ␣1 isoform was made ouabain-sensitive. Mice with the ouabainsensitive ''human-like'' ␣1 isoform and an ouabain-resistant ␣2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the ␣1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the ␣ isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides. adrenocorticotropic hormone ͉ hypertension ͉ endogenous cardiac glycosides

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Section: Discussionmentioning

confidence: 99%

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Dostanic-Larson

Huysse

Lorenz

et al. 2005

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

175

190

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“…Typically the most successful approach was to amplify first the whole region with primers S409 and rATPc and to reamplify smaller fragments for sequencing. Because the gene sequences of the examined insect orders have differing length and positions of introns, we quickly abandoned the DNA-based approach used by previous workers (19,(23)(24)(25)(26) and used RT-PCR instead. RNA was transcribed into cDNA with a 17polyT-primer and SuperScript III reverse transcriptase (Invitrogen) according to manufacturer protocols.…”

Section: Methodsmentioning

confidence: 99%

“…Molecular investigations later demonstrated that this insensitivity may be explained in the monarch butterfly, at least in part, by an amino acid substitution of asparagine for histidine at position 122 (N122H) in the first extracellular loop of the Na,KATPase (19,23). In vitro expression of the Drosophila melanogaster Na,K-ATPase α-subunit with the N122H replacement transfected into HEK cells resulted in increased resistance to ouabain (19).…”

mentioning

confidence: 99%

Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase

Dobler

Dalla

Wagschal

et al. 2012

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

266

288

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The extent of convergent molecular evolution is largely unknown, yet is critical to understanding the genetics of adaptation. Target site insensitivity to cardenolides is a prime candidate for studying molecular convergence because herbivores in six orders of insects have specialized on these plant poisons, which gain their toxicity by blocking an essential transmembrane carrier, the sodium pump (Na,K-ATPase). We investigated gene sequences of the Na,KATPase α-subunit in 18 insects feeding on cardenolide-containing plants (spanning 15 genera and four orders) to screen for amino acid substitutions that might lower sensitivity to cardenolides. The replacement N122H that was previously shown to confer resistance in the monarch butterfly (Danaus plexippus) and Chrysochus leaf beetles was found in four additional species, Oncopeltus fasciatus and Lygaeus kalmii (Heteroptera, Lygaeidae), Labidomera clivicollis (Coleoptera, Chrysomelidae), and Liriomyza asclepiadis (Diptera, Agromyzidae). Thus, across 300 Myr of insect divergence, specialization on cardenolide-containing plants resulted in molecular convergence for an adaptation likely involved in coevolution. Our screen revealed a number of other substitutions connected to cardenolide binding in mammals. We confirmed that some of the particular substitutions provide resistance to cardenolides by introducing five distinct constructs of the Drosophila melanogaster gene into susceptible eucaryotic cells under an ouabain selection regime. These functional assays demonstrate that combined substitutions of Q 111 and N 122 are synergistic, with greater than twofold higher resistance than either substitution alone and >12-fold resistance over the wild type. Thus, even across deep phylogenetic branches, evolutionary degrees of freedom seem to be limited by physiological constraints, such that the same molecular substitutions confer adaptation.insect-plant interactions | specialist herbivores | target site insensitivity | toxin resistance | cardiac glycosides

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“…This is in good agreement with the homogeneity of our in vitro ouabain inhibition assays in seven species. All of the three ATPase a1 gene copies share a replacement of the conserved asparagine by histidine at position 122 [8], a substitution which has been shown to significantly lower the sensitivity of the Na þ /K þ -ATPase to ouabain [7,21,56]. Our preliminary analyses of gene transcripts in the Lygaeinae investigated here (see the electronic supplementary material, duplications and amino acid substitutions must have arisen by stepwise evolution just as in milkweed butterflies, but only a broader sampling of other basal lygaeines and more closely related outgroups can potentially reveal traces of this process.…”

Section: Discussionmentioning

confidence: 99%

Na⁺/K⁺-ATPase resistance and cardenolide sequestration: basal adaptations to host plant toxins in the milkweed bugs (Hemiptera: Lygaeidae: Lygaeinae)

Bramer¹,

Dobler²,

Deckert

et al. 2015

Proc. R. Soc. B.

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Despite sequestration of toxins being a common coevolutionary response to plant defence in phytophagous insects, the macroevolution of the traits involved is largely unaddressed. Using a phylogenetic approach comprising species from four continents, we analysed the ability to sequester toxic cardenolides in the hemipteran subfamily Lygaeinae, which is widely associated with cardenolide-producing Apocynaceae. In addition, we analysed cardenolide resistance of their Na þ /K þ -ATPases, the molecular target of cardenolides. Our data indicate that cardenolide sequestration and cardenolide-resistant Na þ /K þ -ATPase are basal adaptations in the Lygaeinae. In two species that shifted to non-apocynaceous hosts, the ability to sequester was secondarily reduced, yet NaATPase resistance was maintained. We suggest that both traits evolved together and represent major coevolutionary adaptations responsible for the evolutionary success of lygaeine bugs. Moreover, specialization on cardenolides was not an evolutionary dead end, but enabled this insect lineage to host shift to cardenolide-producing plants from distantly related families.

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Molecular basis for the insensitivity of the Monarch (Danaus plexippus) to cardiac glycosides

Cited by 122 publications

References 18 publications

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase

Na⁺/K⁺-ATPase resistance and cardenolide sequestration: basal adaptations to host plant toxins in the milkweed bugs (Hemiptera: Lygaeidae: Lygaeinae)

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Molecular basis for the insensitivity of the Monarch (Danaus plexippus) to cardiac glycosides

Cited by 122 publications

References 18 publications

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase

Na+/K+-ATPase resistance and cardenolide sequestration: basal adaptations to host plant toxins in the milkweed bugs (Hemiptera: Lygaeidae: Lygaeinae)

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Na⁺/K⁺-ATPase resistance and cardenolide sequestration: basal adaptations to host plant toxins in the milkweed bugs (Hemiptera: Lygaeidae: Lygaeinae)