5-HT6 receptor

5-HT₆ receptor je tip 5-HT receptora za koji se vezuje endogeni neurotransmiter serotonin (5-hidroksitriptamin, 5-HT).^[1] On je G protein-spregnuti receptor koji deluje kroz G_s/G_o i posreduje ekscitatornu neurotransmisiju.^[1] HTR6 je i oznaka za humani gen koji kodira ovaj receptor.^[2]

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5-hidroksitriptaminski (serotoninski) receptor 6
Identifikatori
Simboli	HTR6; 5-HT6; 5-HT6R
Vanjski ID	OMIM: 601109 MGI: 1196627 HomoloGene: 673 IUPHAR: 5-HT6 GeneCards: HTR6 Gene
Ontologija gena Molekularna funkcija • aktivnost rodopsinu-sličnog receptora • receptorska aktivnost • aktivnost histaminskog receptora Celularna komponenta • integralno sa ćelijskom membranom • membrana Biološki proces • prenos signala • G-proteinska signalizacija, spregnuta sa cikličnim nukleotidnim sekundarnim glasnikom • sinaptička transmisija
Pregled RNK izražavanja
podaci
Ortolozi
Vrsta	Čovek	Miš
Entrez	3362	15565
Ensembl	ENSG00000158748	ENSMUSG00000028747
UniProt	P50406	Q14AW8
RefSeq (mRNA)	NM_000871	NM_021358
RefSeq (protein)	NP_000862	NP_067333
Lokacija (UCSC)	Chr 1: 19.86 - 19.88 Mb	Chr 4: 138.33 - 138.35 Mb
PubMed pretraga

Distribucija

5-HT₆ receptor je skoro isključivo izražen u mozgu.^[3] On je distribuiran u više oblasti, među kojima su mirisne tuberkule, cerebralni korteks (frontalni i entorinalni regioni), nucleus accumbens, striatum, caudate nucleus, hipokampus, i mali mozak.^[4][5][6] Usled njegove zastupljenosti u ekstrapiramidalnim, limbičnim, i korteksnim regionima smatra se da 5-HT₆ receptor učestvuje u motornoj kontroli, emocionalnosti, kogniciji, i memoriji.^[3][6][7]

Funkcija

Za blokadu centralnih 5-HT₆ receptora je pokazano da povišava glutamatergičku i holinergičku neurotransmisiju u više oblasti mozga,^{[8][9][10][11]} dok aktivacija uvećava opštu GABA signalizaciju.^[12] Antagonizam 5-HT₆ receptora takođe omogućava otpuštanje dopamina i norepinefrina frontalnom korteksu,^[11][13] dok stimulacija ima suprotni efekat.^[12]

Ligandi

Velik broj selektivnih 5-HT₆ liganda je razvijen.^{[14][15][16][17][18][19][20]}

Puni agonisti

• EMD-386,088 - potentan i selektivan 5HT₆ agonist (EC₅₀ 1nM)^[21]
• 2-Etil-5-metoksi-N,N-dimetiltriptamin (EMDT)^[22]
• WAY-181,187^[12]
• WAY-208,466^[12]
• N1-(6-hloroimidazo[2,1-b][1,3]tiazol-5-sulfonil)triptamin (jedinjenje 11q)^[23]
• N-(inden-5-il)imidazotiazol-5-sulfonamid (43): K_i = 4.5nM, EC₅₀ = 0.9nM, E_max = 98%^[24]
• E-6837 - Pun agonist na ljudskim 5-HT₆ receptorima

Parcijalni agonisti

• E-6801^[25]
• E-6837^[26]

Antagonisti

• BVT-5182^[27]
• BVT-74316^[28]
• EGIS-12233 - mešoviti 5-HT₆ / 5-HT₇ antagonist
• Latrepirdin (nije selektivan)^[29] i analozi^[30]
• Lu AE58054
• MS-245
• PRX-07034
• SB-258,585
• SB-271,046
• SB-357,134
• SB-399,885
• SB-742,457
• Ro04-6790
• Atipični antipsihotici (olanzapin, asenapin, klozapin)
• WAY-255315 / SAM-315: Ki = 1.1nM, IC = 13 nM^[31]

Povezano

• 5-HT receptor

Reference

1. Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). „Cloning, characterization, and chromosomal localization of a human 5-HT₆ serotonin receptor”. J. Neurochem. 66 (1): 47–56. DOI:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
2. „Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6”.
3. Woolley ML, Marsden CA, Fone KC (February 2004). „5-ht6 receptors”. Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. DOI:10.2174/1568007043482561. PMID 14965245.
4. Kohen R, Metcalf MA, Khan N, et al. (January 1996). „Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor”. Journal of Neurochemistry 66 (1): 47–56. DOI:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.^{[mrtav link]}
5. Ruat M, Traiffort E, Arrang JM, et al. (May 1993). „A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation”. Biochemical and Biophysical Research Communications 193 (1): 268–76. DOI:10.1006/bbrc.1993.1619. PMID 8389146.
6. Gérard C, Martres MP, Lefèvre K, et al. (January 1997). „Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system”. Brain Research 746 (1-2): 207–19. DOI:10.1016/S0006-8993(96)01224-3. PMID 9037500.
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8. Dawson LA, Nguyen HQ, Li P (May 2000). „In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate”. British Journal of Pharmacology 130 (1): 23–6. DOI:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993.
9. Dawson LA, Nguyen HQ, Li P (November 2001). „The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus”. Neuropsychopharmacology 25 (5): 662–8. DOI:10.1016/S0893-133X(01)00265-2. PMID 11682249.
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12. Schechter LE, Lin Q, Smith DL, et al. (May 2008). „Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466”. Neuropsychopharmacology 33 (6): 1323–35. DOI:10.1038/sj.npp.1301503. PMID 17625499.
13. Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). „5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex”. Synapse 51 (2): 158–64. DOI:10.1002/syn.10288. PMID 14618683.
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20. Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). „Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT₆ receptor ligands”. Org. Biomol. Chem. 6 (20): 3795–810. DOI:10.1039/b808641a. PMID 18843410.
21. Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H (October 2005). „2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT₆ receptor agonists”. Bioorg. Med. Chem. Lett. 15 (19): 4230–4. DOI:10.1016/j.bmcl.2005.06.067. PMID 16055331.
22. Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (2000). „2-Substituted tryptamines: agents with selectivity for 5-HT₆ serotonin receptors”. J. Med. Chem. 43 (5): 1011–8. DOI:10.1021/jm990550b. PMID 10715164.
23. Cole DC, Stock JR, Lennox WJ, Bernotas RC, Ellingboe JW, Boikess S, Coupet J, Smith DL, Leung L, Zhang GM, Feng X, Kelly MF, Galante R, Huang P, Dawson LA, Marquis K, Rosenzweig-Lipson S, Beyer CE, Schechter LE (November 2007). „Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist”. Journal of Medicinal Chemistry 50 (23): 5535–8. DOI:10.1021/jm070521y. PMID 17948978.
24. Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (2009). „Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists”. J. Med. Chem. 52 (3): 675–87. DOI:10.1021/jm8009469. PMID 19159187.
25. Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (August 2006). „Efficacy of selective 5-HT₆ receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways”. Br. J. Pharmacol. 148 (8): 1133–43. DOI:10.1038/sj.bjp.0706827. PMC 1752021. PMID 16865095.
26. Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Mercé R, Holenz J, Vrang N, Sørensen RV, Heal D, Buschmann H, Pauwels PJ (August 2006). „Chronic 5-HT₆ receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats”. Br. J. Pharmacol. 148 (7): 973–83. DOI:10.1038/sj.bjp.0706807. PMC 1751931. PMID 16783408.
27. Hugerth A, Brisander M, Wrange U, Kritikos M, Norrlind B, Svensson M, Bisrat M, Ostelius J (February 2006). „Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT₆ receptor antagonist”. Drug Dev Ind Pharm 32 (2): 185–96. DOI:10.1080/03639040500466122. PMID 16537199.
28. Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 2008). „Selective 5-HT₆ receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders”. Pharmacol. Ther. 117 (2): 207–31. DOI:10.1016/j.pharmthera.2007.08.006. PMID 18068807.
29. Wu, J; Li, Q; Bezprozvanny, I (2008). „Evaluation of Dimebon in cellular model of Huntington's disease.”. Molecular neurodegeneration 3: 15. DOI:10.1186/1750-1326-3-15. PMC 2577671. PMID 18939977.
30. Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Okun IM, Tkachenko SE (June 2009). „Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists”. Bioorganic & Medicinal Chemistry Letters 19 (12): 3183–7. DOI:10.1016/j.bmcl.2009.04.128. PMID 19443217.
31. Liu KG, Robichaud AJ, Bernotas RC, Yan Y, Lo JR, Zhang MY, Hughes ZA, Huselton C, Zhang GM, Zhang JY, Kowal DM, Smith DL, Schechter LE, Comery TA (2010). „5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists”. J Med Chem. 53 (21): 7639-46. PMID 20932009.

Literatura

• Hoyer D, Hannon JP, Martin GR (2002). „Molecular, pharmacological and functional diversity of 5-HT receptors.”. Pharmacol. Biochem. Behav. 71 (4): 533–54. DOI:10.1016/S0091-3057(01)00746-8. PMID 11888546.
• Raymond JR, Mukhin YV, Gelasco A, et al. (2002). „Multiplicity of mechanisms of serotonin receptor signal transduction.”. Pharmacol. Ther. 92 (2-3): 179–212. DOI:10.1016/S0163-7258(01)00169-3. PMID 11916537.
• Van Oekelen D, Luyten WH, Leysen JE (2003). „5-HT2A and 5-HT2C receptors and their atypical regulation properties.”. Life Sci. 72 (22): 2429–49. DOI:10.1016/S0024-3205(03)00141-3. PMID 12650852.
• Dubertret C, Hanoun N, Adès J, et al. (2004). „Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia.”. Am. J. Med. Genet. B Neuropsychiatr. Genet. 126 (1): 10–5. DOI:10.1002/ajmg.b.20120. PMID 15048641.
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• Kohen R, Metcalf MA, Khan N, et al. (1996). „Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.”. J. Neurochem. 66 (1): 47–56. DOI:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
• Orlacchio A, Kawarai T, Paciotti E, et al. (2002). „Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease.”. Neurosci. Lett. 325 (1): 13–6. DOI:10.1016/S0304-3940(02)00221-5. PMID 12023056.
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• Ham BJ, Kim YH, Choi MJ, et al. (2004). „Serotonergic genes and personality traits in the Korean population.”. Neurosci. Lett. 354 (1): 2–5. DOI:10.1016/S0304-3940(03)00753-5. PMID 14698468.
• Bernotas R, Lenicek S, Antane S, et al. (2005). „1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands.”. Bioorg. Med. Chem. Lett. 14 (22): 5499–502. DOI:10.1016/j.bmcl.2004.09.003. PMID 15482912.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). „The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”. Genome Res. 14 (10B): 2121–7. DOI:10.1101/gr.2596504. PMC 528928. PMID 15489334.
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Spoljašnje veze

• „5-HT₆”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2015-04-02.
• MeSH serotonin+6+receptor