Serotoninski transporter

Familija trasportera rastvorka 6 (neurotransmiterski transporter, serotonin), član 4
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
Vrsta	Čovek
Entrez	6532
Ensembl	ENSG00000108576
UniProt	P31645
RefSeq (mRNA)	NM_001045
RefSeq (protein)	NP_001036
Lokacija (UCSC)	Chr 17:; 28.52 - 28.56 Mb
PubMed pretraga	[1]

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

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

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

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

^ ^а ^б Squire, Larry (2008). Fundamental neuroscience (3rd изд.). Amsterdam: Elsevier / Academic Press. стр. 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 (1999). „Alteration of the platelet serotonin transporter in romantic love”. Psychological Medicine. 29 (3): 741—745. PMID 10405096. doi:10.1017/S0033291798007946.
^ van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG (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. PMID 18413401. doi:10.2967/jnumed.107.045518.
^ G, Tamagnan; Alagille D; X, Fu; 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. PMID 15686927. doi:10.1016/j.bmcl.2004.12.014.
^ RJ, Mattson; Catt JD; DJ, Denhart; et al. (2005). „Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors”. Journal of Medicinal Chemistry. 48 (19): 6023—34. PMID 16162005. doi:10.1021/jm0503291.
^ Dalton King H; DJ, Denhart; 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. PMID 17766113. doi:10.1016/j.bmcl.2007.07.083.
^ HD, King; Meng Z; JA, Deskus; et al. (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. PMID 20949929. doi:10.1021/jm100515z.

Literatura

NIH press release: Serotonin Transporter Gene Shown to Influence College Drinking Habits
JP, Roiser; Cook LJ; JD, Cooper; Rubinsztein DC; Sahakian, Barbara (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. PMC 2631647 . PMID 15741482. doi:10.1176/appi.ajp.162.3.609.
S, Ueno (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. PMID 12874600. doi:10.1038/sj.mp.4001336.
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. PMID 14653304. doi:10.1046/j.1601-1848.2003.00052.x.
KM, Smits; Smits LJ; JS, Schouten; 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. PMID 15037864. doi:10.1038/sj.mp.4001488.
HJ, Cho; Meira-Lima I; Q, Cordeiro; 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. PMID 15824745. doi:10.1038/sj.mp.4001663.
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. PMID 15939518. doi:10.1016/j.pnpbp.2005.03.013.
IW, Craig (2007). „The importance of stress and genetic variation in human aggression”. BioEssays. 29 (3): 227—36. PMID 17295220. doi:10.1002/bies.20538.
Rothman RB, Baumann MH, Blough BE, Jacobson AE, Rice KC, Partilla JS (2010). „Evidence for Non-Competitive Modulation of Substrate-Induced Serotonin Release”. Synapse. 64 (11): 862—9. PMC 2941209 . PMID 20842720. doi:10.1002/syn.20804.

[Squire2008-1] а ^б Squire, Larry (2008). Fundamental neuroscience (3rd изд.). Amsterdam: Elsevier / Academic Press. стр. 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 (1999). „Alteration of the platelet serotonin transporter in romantic love”. Psychological Medicine. 29 (3): 741—745. PMID 10405096. doi:10.1017/S0033291798007946.

[4] van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG (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. PMID 18413401. doi:10.2967/jnumed.107.045518.

[pmid15686927-5] G, Tamagnan; Alagille D; X, Fu; 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. PMID 15686927. doi:10.1016/j.bmcl.2004.12.014.

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

[pmid17766113-7] Dalton King H; DJ, Denhart; 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. PMID 17766113. doi:10.1016/j.bmcl.2007.07.083.

[8] HD, King; Meng Z; JA, Deskus; et al. (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. PMID 20949929. doi:10.1021/jm100515z.

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