Serotoninski transporter

Familija trasportera rastvorka 6 (neurotransmiterski transporter, serotonin), član 4
Identifikatori
Simboli	SLC6A4; 5-HTT; 5-HTTLPR; 5HTT; HTT; OCD1; SERT; SERT1; hSERT
Vanjski ID	OMIM: 182138 MGI: 96285 HomoloGene: 817 GeneCards: SLC6A4 Gene
Ontologija gena
Molekularna funkcija	• aktivnost serotonin:natrijum simportera; • proteinsko vezivanje; • aktivnost monoaminskog transmembranskog transportera;
Celularna komponenta	• citozol; • ćelijska membrana; • integralno sa ćelijskom membranom;
Biološki proces	• respons na hipoksiju; • serotoninski transport; • response na nutrijent;
Pregled RNK izražavanja
	podaci
Ortolozi

edit

Serotoninski transporter (SERT) je monoaminski transporter.

SERT je integralni membranski protein koji transportuje neurotransmiter serotonin iz sinaptičkog prostora u presinaptičke neurone. Ovim transportom serotonina posredstvom SERT proteina se završava ciklus dejstva serotonina i dolazi do njegove recirkulacije na način koji je zavistan od natrijuma. Ovaj protein je meta mnogih antidepresivnih lekova, uključujući lekove iz SSRI klase.^[1] On je član familije natrijum:neurotransmiter simportera. Polimorfizmi ponavljajućih segmenata u promoteru ovog gena utiču na brzinu ponovnog preuzimanja serotonina i mogu da budu jedan od činilaca sindroma iznenadne smrti odojčadi, agresivnog ponašanja obolelih od Alchajmerove bolesti, posttraumatskog stresnog poremećaja i sklonosti depresiji kod ljudi koji doživljavaju emocionalne traume.^[2]

Funkcija uredi

Serotonin

Neuroni komuniciraju putem hemijskih glasnika, kao što je serotonin. Serotoninski transporter vraća serotonin iz sinaptičkog rascepa nazad u sinapse. Stoga on prekida dejstvo serotonina i simultano omogućava njegovu ponovnu upotrebu sa presinaptičkog neurona.^[1] Transportni protein putem reciklacije serotonina regulišu njegovu koncentraciju u rascepu, ili sinapsi.

Medicinska ispitivanja su pokazala da su promene metabolizma serotoninskog transportera povezane sa mnoštvom različitih fenomena, uključujući alkoholizam, kliničku depresiju, opsesivno-kompulzivni poremećaj (OCD), romantična osećanja,^[3] hipertenziju i socijalne fobije.^[4]

Serotoninski transporter je takođe prisutan u krvnim pličicama; gde, serotonin funkcioniše kao vasokonstriktivna supstanca.

Farmakologija uredi

SERT premoštava ćelijsku membranu 12 puta. On pripada NE, DA, SERT familijama monoaminskih transportera. Transporteri su značajne biološke mete za agense kojima se tretiraju psihijatrijski poremećaji. Lekovi koji umanjuju vezivanje serotonina za transportere (selektivni inhibitori preuzimanja serotonina, ili SSRI), i ređe oni koji deluju na suprotan način (selektivni pojačavači preuzimanja serotonina, ili SSRE) se koriste za tretiranje mentalnih poremećaja. Oko polovine pacijenata obolelih od OCD se tretira SSRI lekovima. Fluoksetin je primer selektivnog inhibitora preuzimanja serotonina, a tianeptin je primer selektivnog pojačavača preuzimanja serotonina.

12a

Ligandi uredi

DASB
Jedinjenje 4b: Ki = 17 pM; 710-puta i 11.100-puta selektivniji od DAT i NET^[5]
jedinjenje (+)-12a: Ki = 180 pM na hSERT; >1000-puta selektiviji od hDAT, hNET, 5-HT_1A, i 5-HT₆.^[6] Bioizosteri.^[7]
3-cis-(3-Aminociklopentil)indol 8a: Ki = 220 pM^[8]

Reference uredi

↑ ^1,0 ^1,1 Squire et al., edited by Larry (2008). Fundamental neuroscience (3rd izd.). Amsterdam: Elsevier / Academic Press. str. 143-. ISBN 978-0-12-374019-9.
↑ „Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4”.
↑ Marazziti D, Akiskal HS, Rossi A, Cassano GB (May 1999). „Alteration of the platelet serotonin transporter in romantic love”. Psychological Medicine 29 (3): 741-745. DOI:10.1017/S0033291798007946. PMID 10405096.
↑ van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG (May 2008). „Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication–Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-β-(4-Iodophenyl)-Tropane SPECT”. The Journal of Nuclear Medicine 49 (5): 757-763. DOI:10.2967/jnumed.107.045518. PMID 18413401.
↑ Tamagnan G, Alagille D, Fu X, et al. (2005). „Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency”. Bioorg. Med. Chem. Lett. 15 (4): 1131-3. DOI:10.1016/j.bmcl.2004.12.014. PMID 15686927.
↑ Mattson RJ, Catt JD, Denhart DJ, et al. (2005). „Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors”. Journal of Medicinal Chemistry 48 (19): 6023-34. DOI:10.1021/jm0503291. PMID 16162005.
↑ Dalton King H, Denhart DJ, Deskus JA, et al. (2007). „Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor”. Bioorg. Med. Chem. Lett. 17 (20): 5647-51. DOI:10.1016/j.bmcl.2007.07.083. PMID 17766113.
↑ King HD, Meng Z, Deskus JA, et al. (November 2010). „Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors”. Journal of Medicinal Chemistry 53 (21): 7564-72. DOI:10.1021/jm100515z. PMID 20949929.

Literatura uredi

Squire et al., edited by Larry (2008). Fundamental neuroscience (3rd izd.). Amsterdam: Elsevier / Academic Press. str. 143-. ISBN 978-0-12-374019-9.

NIH press release: Serotonin Transporter Gene Shown to Influence College Drinking Habits Arhivirano 2013-06-03 na Wayback Machine-u
Roiser JP, Cook LJ, Cooper JD, Rubinsztein DC, Barbara Sahakian (March 2005). „Association of a Functional Polymorphism in the Serotonin Transporter Gene With Abnormal Emotional Processing in Ecstasy Users”. American Journal of Psychiatry 162 (3): 609-612. DOI:10.1176/appi.ajp.162.3.609. PMC 2631647. PMID 15741482.
Ueno S (2003). „Genetic polymorphisms of serotonin and dopamine transporters in mental disorders”. J. Med. Invest. 50 (1–2): 25-31. PMID 12630565.
Anguelova M, Benkelfat C, Turecki G (2004). „A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior”. Mol. Psychiatry 8 (7): 646-53. DOI:10.1038/sj.mp.4001336. PMID 12874600.
Holmes A, Hariri AR (2004). „The serotonin transporter gene-linked polymorphism and negative emotionality: placing single gene effects in the context of genetic background and environment”. Genes, Brain and Behavior 2 (6): 332-5. DOI:10.1046/j.1601-1848.2003.00052.x. PMID 14653304.
Smits KM, Smits LJ, Schouten JS, et al. (2004). „Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review”. Mol. Psychiatry 9 (5): 433-41. DOI:10.1038/sj.mp.4001488. PMID 15037864.
Cho HJ, Meira-Lima I, Cordeiro Q, et al. (2005). „Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis”. Mol. Psychiatry 10 (8): 771-81. DOI:10.1038/sj.mp.4001663. PMID 15824745.
Serretti A, Benedetti F, Zanardi R, Smeraldi E (2005). „The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments”. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (6): 1074-84. DOI:10.1016/j.pnpbp.2005.03.013. PMID 15939518.
Craig IW (2007). „The importance of stress and genetic variation in human aggression”. BioEssays 29 (3): 227-36. DOI:10.1002/bies.20538. PMID 17295220.
Rothman RB, Baumann MH, Blough BE, Jacobson AE, Rice KC, Partilla JS (November 2010). „Evidence for Non-Competitive Modulation of Substrate-Induced Serotonin Release”. Synapse 64 (11): 862-9. DOI:10.1002/syn.20804. PMC 2941209. PMID 20842720.

[Squire2008-1] 1,0 ^1,1 Squire et al., edited by Larry (2008). Fundamental neuroscience (3rd izd.). Amsterdam: Elsevier / Academic Press. str. 143-. ISBN 978-0-12-374019-9.

[2] „Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4”.

[3] Marazziti D, Akiskal HS, Rossi A, Cassano GB (May 1999). „Alteration of the platelet serotonin transporter in romantic love”. Psychological Medicine 29 (3): 741-745. DOI:10.1017/S0033291798007946. PMID 10405096.

[4] van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG (May 2008). „Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication–Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-β-(4-Iodophenyl)-Tropane SPECT”. The Journal of Nuclear Medicine 49 (5): 757-763. DOI:10.2967/jnumed.107.045518. PMID 18413401.

[pmid15686927-5] Tamagnan G, Alagille D, Fu X, et al. (2005). „Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency”. Bioorg. Med. Chem. Lett. 15 (4): 1131-3. DOI:10.1016/j.bmcl.2004.12.014. PMID 15686927.

[pmid16162005-6] Mattson RJ, Catt JD, Denhart DJ, et al. (2005). „Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors”. Journal of Medicinal Chemistry 48 (19): 6023-34. DOI:10.1021/jm0503291. PMID 16162005.

[pmid17766113-7] Dalton King H, Denhart DJ, Deskus JA, et al. (2007). „Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor”. Bioorg. Med. Chem. Lett. 17 (20): 5647-51. DOI:10.1016/j.bmcl.2007.07.083. PMID 17766113.

[8] King HD, Meng Z, Deskus JA, et al. (November 2010). „Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors”. Journal of Medicinal Chemistry 53 (21): 7564-72. DOI:10.1021/jm100515z. PMID 20949929.

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