title: Evolutionary history and functional characterization of the amphibian xenosensor CAR.
abstract: The xenosensing constitutive androstane receptor (CAR) is widely considered to have arisen in early mammals via duplication of the pregnane X receptor (PXR). We report that CAR emerged together with PXR and the vitamin D receptor from an ancestral NR1I gene already in early vertebrates, as a result of whole-genome duplications. CAR genes were subsequently lost from the fish lineage, but they are conserved in all taxa of land vertebrates. This contrasts with PXR, which is found in most fish species, whereas it is lost from Sauropsida (reptiles and birds) and plays a role unrelated to xenosensing in Xenopus. This role is fulfilled in Xenopus by CAR, which exhibits low basal activity and pronounced responsiveness to activators such as drugs and steroids, altogether resembling mammalian PXR. The constitutive activity typical for mammalian CAR emerged first in Sauropsida, and it is thus common to all fully terrestrial land vertebrates (Amniota). The constitutive activity can be achieved by humanizing just two amino acids of the Xenopus CAR. Taken together, our results provide a comprehensive reconstruction of the evolutionary history of the NR1I subfamily of nuclear receptors. They identify CAR as the more conserved and remarkably plastic NR1I xenosensor in land vertebrates. Nonmammalian CAR should help to dissect the specific functions of PXR and CAR in the metabolism of xeno- and endobiotics in humans. Xenopus CAR is a first reported amphibian xenosensor, which opens the way to toxicogenomic and bioaugmentation studies in this critically endangered taxon of land vertebrates.
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, 55101 Mainz, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Mathäs
authors.forename: Oliver
authors.initials: O
authors.lastname: Burk
authors.forename: Huan
authors.initials: H
authors.lastname: Qiu
authors.forename: Christian
authors.initials: C
authors.lastname: Nusshag
authors.forename: Ute
authors.initials: U
authors.lastname: Gödtel-Armbrust
authors.forename: Dorothea
authors.initials: D
authors.lastname: Baranyai
authors.forename: Shiwei
authors.initials: S
authors.lastname: Deng
authors.forename: Kristin
authors.initials: K
authors.lastname: Römer
authors.forename: Dieudonné
authors.initials: D
authors.lastname: Nem
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010802:Phylogeny; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D014981:Xenopus / Q000235:genetics / Q000378:metabolism
chemical_list: D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid
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