アリール炭化水素受容体、アリール炭化水素レセプター、芳香族炭化水素受容体、ダイオキシン受容体、ダイオキシンレセプター

関: AhR、arylhydrocarbon receptor

同: AHR

WordNet

a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response
an organic compound containing only carbon and hydrogen

PrepTutorEJDIC

=sense organ / 受信装置
炭化水素(水素と炭素のみを含む化学物の総称)
are (面積の単位)の変形

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/04/28 17:59:26」(JST)

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[Wiki en表示]

"AHR" redirects here. For other uses, see Ahr (disambiguation).

The Aryl hydrocarbon receptor (AhR or AHR) is a member of the family of basic helix-loop-helix transcription factors. The physiological ligands of this receptor are unknown, but it binds several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription.

1 Protein functional domains
2 Ligands
3 Signaling pathway
- 3.1 Cytosolic complex
- 3.2 Receptor activation
- 3.3 DNA binding (xenobiotic response element - XRE)
4 Functional role in physiology and toxicology
- 4.1 Role in development
- 4.2 Adaptive response
- 4.3 Toxic response
5 Protein-protein interactions
6 References
7 External links

Protein functional domains

AhR Functional Domains

The AhR protein contains several domains critical for function and is classified as a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors.^[1]^[2] The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of transcription factors.^[3] Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to DNA. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350 amino acids that exhibit a high sequence homology to the protein domains that were originally found in the Drosophila genes period (Per) and single-minded (Sim) and in AhR’s dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT).^[4] The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that heterozygous and homozygous protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain^[5] and contains several conserved residues critical for ligand binding.^[6] Finally, a Q-rich domain is located in the C-terminal region of the protein and is involved in co-activator recruitment and transactivation.^[7]

Ligands

Ahr ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons (polychlorinated dibenzodioxins, dibenzofurans and biphenyls) and polycyclic aromatic hydrocarbons (3-methylcholanthrene, benzo(a)pyrene, benzanthracenes and benzoflavones).^[8]^[9] However, recent work has focused on naturally occurring compounds with the hope of identifying an endogenous ligand.

Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of tryptophan such as indigo dye and indirubin,^[10] tetrapyrroles such as bilirubin,^[11] the arachidonic acid metabolites lipoxin A4 and prostaglandin G,^[12] modified low-density lipoprotein^[13] and several dietary carotinoids.^[9] One assumption made in the search for an endogenous ligand is that the ligand will be a receptor agonist. However, work by Savouret et al. has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.^[14]

Signaling pathway

AhR Signaling Pathway - Denison MS, Nagy SR (2003). "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals". Annu. Rev. Pharmacol. Toxicol. 43: 309-34. *Reprinted, with permission, from the Annual Review of Pharmacology and Toxicology, Volume 43 (c)2003 by Annual Reviews.^[9]

Cytosolic complex

Non-ligand bound Ahr is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90,^[15]^[16] prostaglandin E synthase 3 (Ptges3, p23)^[17]^[18]^[19]^[20] and a single molecule of the immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2),^[21] which was previously identified as AhR interacting protein (AIP)^[22] and AhR-activated 9 (ARA9).^[23] The dimer of Hsp90, along with p23, has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of ARNT.^[5]^[18]^[20]^[24]^[25]^[26] XAP2 interacts with carboxyl-terminal of Hsp90 and binds to the AhR nuclear localization sequence (NLS) preventing the inappropriate trafficking of the receptor into the nucleus.^[27]^[28]^[29]

Receptor activation

Upon ligand binding to AhR, XAP2 is released resulting in exposure of the NLS, which is located in the bHLH region,^[30] leading to importation into the nucleus.^[31] It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.^[26]^[32]^[33]^[34] The activated AhR/ARNT heterodimer complex is then capable of either directly and indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.^[26]^[33]^[35]

DNA binding (xenobiotic response element - XRE)

The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5’-GCGTG-3’^[36] within the consensus sequence 5’-T/GNGCGTGA/CG/CA-3’^[37]^[38] in the promoter region of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5’-GTG-3’ and AhR binding 5’-TC/TGC-3’.^[39]^[40] Recent research suggests that a second type of element termed AHRE-II, 5’-CATG(N6)C[T/A]TG-3’, is capable of indirectly acting with the AhR/ARNT complex.^[41]^[42] Regardless of the response element, the end result is a variety of differential changes in gene expression.

Functional role in physiology and toxicology

Role in development

In terms of evolution, the oldest physiological role of Ahr is in development. Ahr is presumed to have evolved from invertebrates where it served a ligand-independent role in normal development processes.^[43] The Ahr homolog in Drosophila, spineless (ss) is necessary for development of the distal segments of the antenna and leg.^[44]^[45] Ss dimerizes with tango (tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription. Evolution of the receptor in vertebrates resulted in the ability to bind ligand. In developing vertebrates, Ahr seemingly plays a role in cellular proliferation and differentiation.^[46] Despite lacking a clear endogenous ligand, AHR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis,^[47] lymphoid systems,^[48]^[49] T-cells,^[50] neurons,^[51] and hepatocytes.^[52] AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion ^[53] and is involved in megakaryocyte differentiation.^[54]

Adaptive response

The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway.^[55]^[56]^[57] The search for other metabolizing genes induced by Ahr ligands, due to the presence of DREs, has led to the identification of an “Ahr gene battery” of Phase I and Phase II metabolizing enzymes consisting of CYP1A1, CYP1A2, CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1.^[58] Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates Ahr is able to bind and facilitate their biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.^[59]

AhR activation seems to be also important for immunological responses and inhibiting inlammation.^[49]^[60]

Toxic response

Extensions of the adaptive response are the toxic responses elicited by Ahr activation. Toxicity results from two different ways of Ahr signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon benzo(a)pyrene (BaP), a ligand for Ahr, induces its own metabolism and bioactivation to a toxic metabolite via the induction of CYP1A1 and CYP1B1 in several tissues.^[61] The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the “Ahr gene battery.” These global changes in gene expression lead to adverse changes in cellular processes and function.^[62] Microarray analysis has proved most beneficial in understanding and characterizing this response.^[46]^[63]^[64]^[65]

Protein-protein interactions

In addition to the protein interactions mentioned above, AhR has also been shown to interact with RELA,^[66]^[67] cyclin T1,^[68]SRC-1,^[69] retinoblastoma protein,^[70] NRIP1,^[71] estrogen receptor alpha,^[72]^[73] NEDD8^[74] and ARNTL.^[75]

References

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MeSH Aryl+hydrocarbon+receptor

UpToDate Contents

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English Journal

Combined chemical and toxicological long-term monitoring for AhR agonists with SPMD-based virtual organisms in drinking water Danjiangkou Reservoir, China.

Wang J1, Song G2, Li A2, Henkelmann B3, Pfister G3, Tong AZ4, Schramm KW5.
Chemosphere.Chemosphere.2014 Aug;108:306-13. doi: 10.1016/j.chemosphere.2014.01.056. Epub 2014 Feb 16.
SPMD-based virtual organisms (VOs) were employed for time-integrating, long-term sampling combined biological and chemical analyses for exposure assessment of hydrophobic organic pollutants (HOPs) in a drinking water reservoir, China. The SPMDs were deployed at four and five sites in the Danjiangkou
PMID 24548649

Cloning of circadian rhythmic pathway genes and perturbation of oscillation patterns in endocrine disrupting chemicals (EDCs)-exposed mangrove killifish Kryptolebias marmoratus.

Rhee JS1, Kim BM2, Lee BY2, Hwang UK3, Lee YS4, Lee JS5.
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP.Comp Biochem Physiol C Toxicol Pharmacol.2014 Aug;164:11-20. doi: 10.1016/j.cbpc.2014.04.001. Epub 2014 Apr 12.
To investigate the effect of endocrine disrupting chemicals (EDCs) on the circadian rhythm pathway, we cloned clock and circadian rhythmic pathway-associated genes (e.g. Per2, Cry1, Cry2, and BMAL1) in the self-fertilizing mangrove killifish Kryptolebias marmoratus. The promoter region of Km-clock h
PMID 24726801

Associations between oxytocin-related genes and autistic-like traits.

Hovey D1, Zettergren A, Jonsson L, Melke J, Anckarsäter H, Lichtenstein P, Westberg L.
Social neuroscience.Soc Neurosci.2014 Aug;9(4):378-86. doi: 10.1080/17470919.2014.897995. Epub 2014 Mar 17.
Oxytocin has repeatedly been shown to influence human behavior in social contexts; also, a relationship between oxytocin and the pathophysiology of autism spectrum disorder (ASD) has been suggested. In the present study, we investigated single-nucleotide polymorphisms (SNPs) in the oxytocin gene (OX
PMID 24635660

Japanese Journal

〈Original Papers〉ダイオキシン受容体型転写因子AhRの転写活性化コア領域

岡南政宏,藤谷純也,阿野貴司
Memoirs of the Faculty of Biology-Oriented Science and Technology of Kinki University (28), 1-11, 2011-9
… Fujitani, Jun-ya[要旨] AhR(arylhydrocarbon receptor)は、bHLHPASファミリーに属する受容体型転写因子である。 … [Abstract] Aryl hydrocarbon receptor (AhR) is a ligand-activated, bHLH-PAS-type anscription factor that regulates genes involved in xenobiotic metabolism, cellular proliferation and differentiation. …
NAID 120003460254

中国・北京及び日本・金沢の大気が示すAhR活性化作用へのPAH類及びダイオキシン類の寄与

戸次加奈江,滝上英孝,鈴木剛,唐寧,鳥羽陽,亀田貴之,早川和一
環境化学 : journal of environmental chemistry 21(1), 27-33, 2011-03-24
NAID 10028172072

Related Pictures

★リンクテーブル★

リンク元	「ダイオキシン受容体」「arylhydrocarbon receptor」「芳香族炭化水素受容体」「アリール炭化水素受容体」「ダイオキシンレセプター」
拡張検索	「aryl hydrocarbon receptor nuclear translocator」
関連記事	「aryl hydrocarbon」

「ダイオキシン受容体」

Aryl hydrocarbon receptor
Identifiers
Symbols	AHR; bHLHe76
External IDs	OMIM: 600253 MGI: 105043 HomoloGene: 1224 GeneCards: AHR Gene
Gene Ontology
Molecular function	• DNA binding; • DNA binding; • sequence-specific DNA binding transcription factor activity; • sequence-specific distal enhancer binding RNA polymerase II transcription factor activity; • signal transducer activity; • receptor activity; • ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity; • protein binding; • transcription factor binding; • sequence-specific DNA binding; • transcription regulatory region DNA binding; • protein heterodimerization activity; • protein dimerization activity; • Hsp90 protein binding;
Cellular component	• nucleus; • transcription factor complex; • nucleolus; • cytoplasm; • cytosol; • cytosolic aryl hydrocarbon receptor complex;
Biological process	• negative regulation of transcription from RNA polymerase II promoter; • cell morphogenesis; • ovarian follicle development; • blood vessel development; • patterning of blood vessels; • liver development; • blood vessel remodeling; • immune system process; • negative regulation of systemic arterial blood pressure; • circumferential growth involved in left ventricle morphogenesis; • regulation of transcription, DNA-dependent; • regulation of transcription, DNA-dependent; • regulation of transcription from RNA polymerase II promoter; • transcription from RNA polymerase II promoter; • xenobiotic metabolic process; • apoptotic process; • response to stress; • cell cycle; • response to xenobiotic stimulus; • regulation of gene expression; • response to organic cyclic compound; • intracellular receptor mediated signaling pathway; • prostate gland development; • regulation of B cell proliferation; • response to estradiol stimulus; • embryonic hemopoiesis; • post-embryonic hemopoiesis; • positive regulation of growth rate; • camera-type eye development; • T cell homeostasis; • positive regulation of cell size; • positive regulation of transcription, DNA-dependent; • positive regulation of RNA polymerase II transcriptional preinitiation complex assembly; • negative regulation of vasoconstriction; • blood vessel morphogenesis; • spleen development; • smooth muscle tissue development; • regulation of blood vessel size; • negative regulation of necrotic cell death; • venous blood vessel development; • kidney morphogenesis; • common bile duct development; • cellular response to glucocorticoid stimulus; • glomerulus morphogenesis;
	Sources: Amigo / QuickGO
Orthologs
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