Histaminski receptor H₄

Histaminski receptor H4
Identifikatori
Simboli	HRH4; AXOR35; BG26; GPCR105; GPRv53; H4; H4R; HH4R
Vanjski ID	OMIM: 606792 MGI: 2429635 HomoloGene: 11002 IUPHAR: H4 GeneCards: HRH4 Gene
Ontologija gena
Molekularna funkcija	• aktivnost prenosa signala • receptorska aktivnost • aktivnost G protein spregnutog receptora • aktivnost histaminskog receptora
Celularna komponenta	• membranska frakcija • ćelijska membrana • integralno sa membranom
Biološki proces	• inflamatorni respons • biološki proces
Ortolozi

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Histaminski receptor H₄ pripada histaminskim receptorima i član je familije G protein spregnutih receptora.^[1]^[2]^[3]

Distribucija u tkivu

Receptor H₄ visoko je izražen u koštanoj srži i belim krvnim zrncima. On reguliše otpuštanje neutrofila iz kičmene moždine i naknadnu infiltraciju u zimosanom indukovanom mišjem modelu zapaljenja plućne maramice.^[4] On je takođe izražen u crevima, jetri, plućima, slezini, testisima, timusu, krajnicima, i dušniku.^[5]

Funkcija

Pokazano je da receptor H₄ posreduje hemotaksu mastocita.^[6] Smatra se da do toga dolazi putem mehanizma G_i spregnutog smanjenja cAMP.^[7]

Struktura

Trodimenzionalna struktura receptora H₄ nije rešena usled problema vezanih za GPCR kristalizaciju. Razvijen je niz strukturnih modela receptora H₄ za različite svrhe. Prvi model receptora H₄^[8] formiran je putem homolognog modelovanja baziranog na kristalnoj strukturi goveđeg rodopsina.^[9] Taj model je korišten za interpretaciju podataka mutageneze pojedinih mesta sekvence, čime je otkriven značaj Asp94 (3.32) i Glu182 (5.46) ostataka za vezivanje liganda i aktivaciju receptora.

Drugi strukturni model receptora H₄ baziran na rodopsinu uspešno je korišten za identifikaciju novih liganda.^[10]

Nedavni progres u GPCR kristalizaciji, posebno određivanje strukture ljudskog histaminskog receptora H₁ u kompleksu sa doksepinom^[11] će uticati na poboljšanje kvaliteta novih strukturnih modela receptora H₄.

Ligandi

Agonisti

4-Metilhistamin
VUF-8430 (2-[(Aminoiminometil)amino]etil estar karbamimidotionske kiseline)
OUP-16

Antagonisti

Tioperamid
JNJ 7777120
VUF-6002 (1-[(5-hloro-1H-benzimidazol-2-il)karbonil]-4-metilpiperazin)
A987306
A943931

Terapeutski potencijal

Inhibicija receptora H₄ može se koristiti u tretiranju astme i alergije.^[7]

Visoko selektivni antagonist histaminskog receptora H₄ VUF-6002 oralno je aktivan i inhibira aktivnost mastocita i eozinofila in vivo.^[12] On ima antiinflamatorne i antihiperalgezivne efekte.^[13]

Reference

↑ Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S (2000). „Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes”. J. Biol. Chem. 275 (47): 36781–6. DOI:10.1074/jbc.M006480200. PMID 10973974.
↑ Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K (2000). „Molecular cloning and characterization of a new human histamine receptor, HH4R”. Biochem. Biophys. Res. Commun. 279 (2): 615–20. DOI:10.1006/bbrc.2000.4008. PMID 11118334.
↑ Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF (2001). „Discovery of a novel member of the histamine receptor family” (abstract). Mol. Pharmacol. 59 (3): 427–33. PMID 11179435. Arhivirano iz originala na datum 2008-10-07. Pristupljeno 2014-05-03.
↑ Takeshita K, Bacon KB, Gantner F (2004). „Critical role of L-selectin and histamine H4 receptor in zymosan-induced neutrophil recruitment from the bone marrow: comparison with carrageenan”. J. Pharmacol. Exp. Ther. 310 (1): 272–80. DOI:10.1124/jpet.103.063776. PMID 14996947.
↑ Bioreagents.com: Histamine H4 Receptor
↑ Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP (2003). „Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells”. J. Pharmacol. Exp. Ther. 305 (3): 1212–21. DOI:10.1124/jpet.102.046581. PMID 12626656.
↑ ^7,0 ^7,1 InterPro: IPR008102 Histamine H4 receptor
↑ Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ (July 2002). „Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor”. Mol. Pharmacol. 62 (1): 38–47. PMID 12065753.
↑ Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (August 2000). „Crystal structure of rhodopsin: A G protein-coupled receptor”. Science 289 (5480): 739–45. DOI:10.1126/science.289.5480.739. PMID 10926528.
↑ Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, Noszál B, Falus A, Keseru GM (June 2008). „Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening”. J. Med. Chem. 51 (11): 3145–53. DOI:10.1021/jm7014777. PMID 18459760. Lay summary – blog.mcule.com.
↑ Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S (June 2011). „Structure of the human histamine H(1) receptor complex with doxepin”. Nature 475 (7354). DOI:10.1038/nature10236. PMID 21697825.
↑ Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ. Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. European Journal of Pharmacology. 2005 Oct 17;522(1-3):130-8. PMID 16213481
↑ Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R. Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation.European Journal of Pharmacology. 2007 Jun 1;563(1-3):240-4. PMID 17382315

Vanjske veze

MeSH HRH4+protein,+human

[pmid10973974-1] Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S (2000). „Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes”. J. Biol. Chem. 275 (47): 36781–6. DOI:10.1074/jbc.M006480200. PMID 10973974.

[pmid11118334-2] Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K (2000). „Molecular cloning and characterization of a new human histamine receptor, HH4R”. Biochem. Biophys. Res. Commun. 279 (2): 615–20. DOI:10.1006/bbrc.2000.4008. PMID 11118334.

[pmid11179435-3] Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF (2001). „Discovery of a novel member of the histamine receptor family” (abstract). Mol. Pharmacol. 59 (3): 427–33. PMID 11179435. Arhivirano iz originala na datum 2008-10-07. Pristupljeno 2014-05-03.

[pmid14996947-4] Takeshita K, Bacon KB, Gantner F (2004). „Critical role of L-selectin and histamine H4 receptor in zymosan-induced neutrophil recruitment from the bone marrow: comparison with carrageenan”. J. Pharmacol. Exp. Ther. 310 (1): 272–80. DOI:10.1124/jpet.103.063776. PMID 14996947.

[otherorgans-5] Bioreagents.com: Histamine H4 Receptor

[pmid12626656-6] Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP (2003). „Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells”. J. Pharmacol. Exp. Ther. 305 (3): 1212–21. DOI:10.1124/jpet.102.046581. PMID 12626656.

[interpro-7] 7,0 ^7,1 InterPro: IPR008102 Histamine H4 receptor

[pmid12065753-8] Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ (July 2002). „Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor”. Mol. Pharmacol. 62 (1): 38–47. PMID 12065753.

[pmid10926528-9] Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (August 2000). „Crystal structure of rhodopsin: A G protein-coupled receptor”. Science 289 (5480): 739–45. DOI:10.1126/science.289.5480.739. PMID 10926528.

[pmid18459760-10] Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, Noszál B, Falus A, Keseru GM (June 2008). „Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening”. J. Med. Chem. 51 (11): 3145–53. DOI:10.1021/jm7014777. PMID 18459760. Lay summary – blog.mcule.com.

[pmid21697825-11] Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S (June 2011). „Structure of the human histamine H(1) receptor complex with doxepin”. Nature 475 (7354). DOI:10.1038/nature10236. PMID 21697825.

[12] Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ. Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. European Journal of Pharmacology. 2005 Oct 17;522(1-3):130-8. PMID 16213481

[13] Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R. Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation.European Journal of Pharmacology. 2007 Jun 1;563(1-3):240-4. PMID 17382315

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