Beta-2 adrenergički receptor

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Beta-2 adrenergički receptor, surface

Kristalografska struktura β₂-adrenergičkog receptor prikazanog kao zeleni crtež i vezanog parcijalnog inverznog agonista karazolol liganda kao sfere (atom ugljenika = siv, kiseonik = crven, azot = plav). Fosfolipidni dvosloj je prikazan kao plave sfere (glave fosfatnih grupa) i žute linije (lipidni bočni lanci).^[1]^[2]

Identifikatori

Simboli

ADRB2; ADRB2R; ADRBR; B2AR; BAR; BETA2AR

Vanjski ID

OMIM: 109690 MGI: 87938 HomoloGene: 30948 IUPHAR: β₂-adrenoceptor GeneCards: ADRB2 Gene

Ontologija gena
Molekularna funkcija	• rodopsinu-slična receptorska aktivnost • receptorska aktivnost • aktivnost beta2-adrenergičkog receptora • proteinsko vezivanje • proteinska homodimerizaciona aktivnost • vezivanje norepinefrina
Celularna komponenta	• membranska frakcija • nukleus • lizozom • endozom • membrana plazme • integralno sa membranom plazme • apikalna membrana plazme • receptorski kompleks
Biološki proces	• aktivacija MAPK aktivnosti • dijetom indukovana termogeneza • norepinefrin-epinefrin vazodilacija tokom regulacije krvnog pritiska • regulacija transporta natrijumskih jona • arestin posredovana desenziticija GPCR proteinskog signalnog puta • receptorom-posredovana endocitoza • aktivacija transmembranski receptor proteinske tirozin kinaze (dimerizacija) • G-protein spregnuti receptorski signalni put • aktivacija adenilat ciklaze • kaskada proteinskih kinaza • endozom u lizozom transport • respons na hladnoću • pozitivna regulacija koštane mineralizacije • generisanje toplote • negativna regulacija veličine tela • pozitivna regulacija MAPKKK kaskade • resorpcija kosti • pozitivna regulacija transkripcije iz RNK polimeraze II promotera • negativna regulacija konstrukcije glatkih mišića • diferencijacija smeđih masnih ćelija

Pregled RNK izražavanja

podaci

Ortolozi

Vrsta

Čovek

Miš

Entrez

154

11555

Ensembl

ENSG00000169252

ENSMUSG00000045730

UniProt

P07550

Q8BH38

RefSeq (mRNA)

NM_000024

NM_007420

RefSeq (protein)

NP_000015

NP_031446

Lokacija (UCSC)

Chr 5:
148.19 - 148.19 Mb

Chr 18:
62.3 - 62.31 Mb

PubMed pretraga

[1]

[2]

Beta-2 adrenergički receptor (β₂ adrenoreceptor), takođe poznat kao ADRB2, je beta-adrenergički receptor.^[3]

Gen

ADRB2 gen ne sadrži introne. Razne polimorfne forme, tačke mutacija, i/ili umanjeno izražavanje ovog gena su vezani sa noćnom astmom, gojaznošću i tip 2 dijabetesom.^[4]

Struktura

3D kristalografska struktura β₂-adrenergičkog receptora je bila određena (2R4R, 2R4S, 2RH1).^[5]^[1]^[2]

Mehanizam

Ovaj receptor je direktno vezan sa jednim od njegovih ultimatnih efektora, klasom C L-tip kalcijumskim kanalom Ca_V1.2. Ovaj receptor-kanal kompleks je spregnut sa G_s G proteinom, koji aktivira adenilil ciklazu, katalizujući formaciju cikličnog adenozin monofosfata (cAMP), koji onda aktivira proteinsku kinazu A, i kontra-balansira fosfatazu PP2A. Kompozicija signalnog kompleksa omogućava mehanizam koji proizvodi specifičnu i brzu signalizaciju. Biofizički i molekularni model sa dva stanja je bio predložen da bi se objasnila pH i REDOX senzitivnost ovog i drugih GPCR receptora.^[6]

Za beta-2 adrenergički receptor je takođe bilo utvrđeno da se spreže sa G_i. Moguće je da se time stvara mehanizam kojim je respons na ligande visoko lokalizovan unutar ćelija. U kontrastu s tim, Beta-1 adrenergički receptori se sprežu samo sa G_s, i njihova stimulacija rezultira u difuznijem ćelijskom responsu.^[7] Postoje indikacije da je ovo posredovano cAMP indukovanom PKA fosforilacijom receptora.^[8]

Literatura

↑ ^1,0 ^1,1 PDB 2RH1; Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). „High-resolution crystal structure of an engineered human β₂-adrenergic G protein-coupled receptor”. Science 318 (5854): 1258–65. DOI:10.1126/science.1150577. PMID 17962520.
↑ ^2,0 ^2,1 Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007). „GPCR engineering yields high-resolution structural insights into β₂-adrenergic receptor function”. Science 318 (5854): 1266–73. DOI:10.1126/science.1150609. PMID 17962519.
↑ „Entrez Gene: ADRB1 adrenergic, beta-1-, receptor”.
↑ „Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface”.
↑ Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007). „Crystal structure of the human β₂-adrenergic G-protein-coupled receptor”. Nature 450 (7168): 383–7. DOI:10.1038/nature06325. PMID 17952055.
↑ Rubenstein LA, Zauhar RJ, Lanzara RG (2006). „Molecular dynamics of a biophysical model for β₂-adrenergic and G protein-coupled receptor activation”. J. Mol. Graph. Model. 25 (4): 396–409. DOI:10.1016/j.jmgm.2006.02.008. PMID 16574446.
↑ Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (November 2000). „G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels”. Biophys. J. 79 (5): 2547–56. DOI:10.1016/S0006-3495(00)76495-2. PMC 1301137. PMID 11053129.
↑ Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ (August 2002). „Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system”. J. Biol. Chem. 277 (34): 31249–56. DOI:10.1074/jbc.M202753200. PMID 12063255.

Dodatna literatura

Frielle T, Caron MG, Lefkowitz RJ (1989). „Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning.”. Clin. Chem. 35 (5): 721–5. PMID 2541947.
Taylor DR, Kennedy MA (2002). „Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma.”. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice 1 (3): 165–74. PMID 12083965.
Thibonnier M, Coles P, Thibonnier A, Shoham M (2002). „Molecular pharmacology and modeling of vasopressin receptors.”. Prog. Brain Res. 139: 179–96. DOI:10.1016/S0079-6123(02)39016-2. PMID 12436935.
Ge D, Huang J, He J, et al. (2005). „beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese.”. Ann. Hum. Genet. 69 (Pt 1): 36–44. DOI:10.1046/j.1529-8817.2003.00093.x. PMID 15638826.
Muszkat M (2007). „Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9.”. Clin. Pharmacol. Ther. 82 (2): 215–8. DOI:10.1038/sj.clpt.6100142. PMID 17329986.
Bucens D, Pain MC (1976). „Influence of hematocrit, blood gas tensions, and pH on pressure-flow relations in the isolated canine lung.”. Circ. Res. 37 (5): 588–96. PMID 154.
von Zastrow M, Kobilka BK (1992). „Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors.”. J. Biol. Chem. 267 (5): 3530–8. PMID 1371121.
Gope R, Gope ML, Thorson A, et al. (1992). „Genetic changes at the beta-2-adrenergic receptor locus on chromosome 5 in human colorectal carcinomas.”. Anticancer Res. 11 (6): 2047–50. PMID 1663718.
Bouvier M, Guilbault N, Bonin H (1991). „Phorbol-ester-induced phosphorylation of the beta 2-adrenergic receptor decreases its coupling to Gs.”. FEBS Lett. 279 (2): 243–8. DOI:10.1016/0014-5793(91)80159-Z. PMID 1848190.
Yang-Feng TL, Xue FY, Zhong WW, et al. (1990). „Chromosomal organization of adrenergic receptor genes.”. Proc. Natl. Acad. Sci. U.S.A. 87 (4): 1516–20. DOI:10.1073/pnas.87.4.1516. PMC 53506. PMID 2154750.
Hui KK, Yu JL (1989). „Effects of protein kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, on beta-2 adrenergic receptor activation and desensitization in intact human lymphocytes.”. J. Pharmacol. Exp. Ther. 249 (2): 492–8. PMID 2470898.
Hen R, Axel R, Obici S (1989). „Activation of the beta 2-adrenergic receptor promotes growth and differentiation in thyroid cells.”. Proc. Natl. Acad. Sci. U.S.A. 86 (12): 4785–8. DOI:10.1073/pnas.86.12.4785. PMC 287358. PMID 2471981.
O'Dowd BF, Hnatowich M, Caron MG, et al. (1989). „Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor.”. J. Biol. Chem. 264 (13): 7564–9. PMID 2540197.
Bristow MR, Hershberger RE, Port JD, et al. (1989). „Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium.”. Mol. Pharmacol. 35 (3): 295–303. PMID 2564629.
Emorine LJ, Marullo S, Delavier-Klutchko C, et al. (1987). „Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization.”. Proc. Natl. Acad. Sci. U.S.A. 84 (20): 6995–9. DOI:10.1073/pnas.84.20.6995. PMC 299215. PMID 2823249.
Chung FZ, Wang CD, Potter PC, et al. (1988). „Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation.”. J. Biol. Chem. 263 (9): 4052–5. PMID 2831218.
Yang SD, Fong YL, Benovic JL, et al. (1988). „Dephosphorylation of the beta 2-adrenergic receptor and rhodopsin by latent phosphatase 2.”. J. Biol. Chem. 263 (18): 8856–8. PMID 2837466.
Kobilka BK, Dixon RA, Frielle T, et al. (1987). „cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor.”. Proc. Natl. Acad. Sci. U.S.A. 84 (1): 46–50. DOI:10.1073/pnas.84.1.46. PMC 304138. PMID 3025863.
Chung FZ, Lentes KU, Gocayne J, et al. (1987). „Cloning and sequence analysis of the human brain beta-adrenergic receptor. Evolutionary relationship to rodent and avian beta-receptors and porcine muscarinic receptors.”. FEBS Lett. 211 (2): 200–6. DOI:10.1016/0014-5793(87)81436-9. PMID 3026848.
„β₂-adrenoceptor”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2015-01-12.

Transmembranski receptor: G protein spregnuti receptori

Klasa A: Rodopsinu slični

Neurotransmiter

Adrenergički	α1 (A, B, D) • α2 (A, B, C) • β1 • β2 • β3
Purinski	Adenozinski (A1, A2A, A2B, A3) • P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
Serotoninski	(svi osim 5-HT3) 5-HT1 (A, B, D, E, F) • 5-HT2 (A, B, C) • 5-HT (4, 5A, 6, 7)
Drugi	Acetilholin (M1, M2, M3, M4, M5) • Dopamin (D1, D2, D3, D4, D5) • Histamin (H1, H2, H3, H4) • Melatonin (1A, 1B, 1C) • TAAR (1, 2, 3, 5, 6, 8, 9)

Metaboliti i
signalni molekuli

Eikozanoidni	CysLT (1, 2) • LTB4 (1, 2) • FPRL1 • OXE • Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) • Prostaciklin • Tromboksan
Drugi	Žučna kiselina • Kanabinoidni (CB1, CB2, GPR (18, 55, 119)) • EBI2 • Estrogen • Slobodna masna kiselina (1, 2, 3, 4) • Laktat • Lizofosfatidna kiselina (1, 2, 3, 4, 5, 6) • Lizofosfolipid (1, 2, 3, 4, 5, 6, 7, 8) • Niacin (1, 2) • Oksoglutarat • PAF • Sfingozin-1-fosfat (1, 2, 3, 4, 5) • Sukcinat

Peptid

Neuropeptidni

B/W (1, 2) • FF (1, 2) • S • Y (1, 2, 4, 5) • Neuromedin (B, U (1, 2)) • Neurotenzin (1, 2)

Drugi

Anafilatoksin (C3a, C5a) • Angiotenzin (1, 2) • Apelin • Bombezin (BRS3, GRPR, NMBR) • Bradikinin (B1, B2) • Hemokin • Holecistokinin (A, B) • Endotelin (A, B) • Formil peptid (1, 2, 3) • FSH • Galanin (1, 2, 3) • GHB receptor • Gonadotropin-oslobađajući hormon (1, 2) • Grelin • Kispeptin • Luteinizirajući hormon/horiogonadotropin • MAS (1, 1L, D, E, F, G, X1, X2, X3, X4) • Melanokortin (1, 2, 3, 4, 5) • MCHR (1, 2) • Motilin • Opioidni (δ, κ, μ, Nociceptin & ζ, ali ne σ) • Oreksin (1, 2) • Oksitocin • Prokineticin (1, 2) • Prolaktin-oslobađajući peptid • Relaksin (1, 2, 3, 4) • Somatostatin (1, 2, 3, 4, 5) • Tahikinin (1, 2, 3) • Tirotropin • Tirotropin-oslobađajući hormon • Urotenzin-II • Vazopresin (1A, 1B, 2)

Razno

Orfan	GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Drugi	Adrenomedulin • Mirisni • Opsin (3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH) • Proteazom-aktivirani (1, 2, 3, 4) • SREB (1, 2, 3)

Klasa B: Sekretinu slični

Orfan	GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Drugi	Moždano specifični angiogenezni inhibitor (1, 2, 3) • Cadherin (1, 2, 3) • Kalcitonin • CALCRL • CD97 • Kortikotropin-oslobađajući hormon (1, 2) • EMR (1, 2, 3) • Glukagon (GR, GIPR, GLP1R, GLP2R) • Hormon rasta oslobađajući hormon • PACAPR1 • GPR • Latrofilin (1, 2, 3, ELTD1) • Metuselah-slični proteini • Paratiroidni hormon (1, 2) • Sekretin • Vazoaktivni intestinalni peptid (1, 2)

Orfan

GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)

Drugi

Moždano specifični angiogenezni inhibitor (1, 2, 3) • Cadherin (1, 2, 3) • Kalcitonin • CALCRL • CD97 • Kortikotropin-oslobađajući hormon (1, 2) • EMR (1, 2, 3) • Glukagon (GR, GIPR, GLP1R, GLP2R) • Hormon rasta oslobađajući hormon • PACAPR1 • GPR • Latrofilin (1, 2, 3, ELTD1) • Metuselah-slični proteini • Paratiroidni hormon (1, 2) • Sekretin • Vazoaktivni intestinalni peptid (1, 2)

Klasa C: Metabotropni
glutamat / feromon

Ukus	TAS1R (1, 2, 3) • TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Drugi	Kalcijum-detektujući receptor • GABA B (1, 2) • Glutamatni receptor (Metabotropni glutamat (1, 2, 3, 4, 5, 6, 7, 8)) • GPRC6A • GPR (156, 158, 179) • RAIG (1, 2, 3, 4)

Klasa F:
Frizzled / Zaglađeni

Uvojiti	Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Zaglađeni	Zaglađeni

B trdu: peptidi (nrpl/grfl/cytl/horl), receptori (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd, signalni putevi (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)