Serotonin transporters

Serotonin transporters
Properties of human protein
Mass / length primary structure	630 amino acids
Identifier
Gene name	SLC6A4
External IDs	OMIM : 182138 ; UniProt : P31645 ;
Transporter classification
TCDB	2.A.22.1.1
designation	Sodium Neurotransmitter Symporter
Occurrence
Parent taxon	Bilateria

The serotonin transporter ( SERT ), also called 5-hydroxytryptamine transporter ( 5-HTT ), is a protein of the cell membrane that enables the transport of the tissue hormone and neurotransmitter serotonin into the cell . One of the main functions of this transport protein , which belongs to the family of sodium neurotransmitter symporters , is to remove released serotonin from the synaptic cleft and thus terminate the effect of serotonin.

An inhibition of the serotonin transporter or even a reversal of their transport direction is partly responsible for the effect of some psychostimulants such as cocaine and MDMA ( ecstasy ). Selective inhibitors of the serotonin transporter, the so-called Selective Serotonin Reuptake Inhibitors (SSRI), are used in particular in the treatment of depression .

The transport equation is:

Serotonin (outside) + Na ⁺ (outside) Serotonin (inside) + Na ⁺ (inside)

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The inward-directed transport of serotonin is driven as a secondary active process by the sodium-potassium-ATPase .

Occurrence

The serotonin transporter is widespread in the animal kingdom . Homologues of the human serotonin transporter could be detected in relatively primitive animal species such as the nematode Caenorhabditis elegans . A homolog of this transporter has also been found in prokaryotes .

genetics

The human serotonin transporter is a as SLC6A4 designated gene on chromosome 17 in the locus encodes Q11.1-q12. The gene contains 14 different exons , which are responsible for different splice variants of the serotonin transporter. A polymorphism in the promoter region is associated with an increased incidence of depression and an increased tendency to suicide .

biochemistry

structure

The serotonin transporter is a transmembrane protein , for which, like other proteins from the family of sodium neurotransmitter symporter, a structure consisting of twelve helices spanning the cell membrane is assumed. This structural feature could previously be detected with the help of crystal structure analysis for related bacterial transporters, such as lactose permease , the glycerol-3-phosphate transporter and the leucine transporter . It is also assumed that the serotonin transporter exists as an oligomeric complex of several molecules in the cell membrane.

Activation and regulation

The mechanism of activation and regulation is not yet fully understood. However, crystal structure data from bacterial relatives of the serotonin transporter provided important insights.

The serotonin transporter has a binding site for Na ⁺ , Cl ^- and serotonin. After the simultaneous attachment of these three molecules to a pore of the transmembrane protein accessible from the extracellular space , a change in conformation occurs. After this conformational change, the connection between the Na ⁺ , Cl ^- and serotonin binding site to the extracellular space is closed and opened to the intracellular space . Serotonin can be released into the intracellular space through an exchange for K ⁺ . Also, dopamine , although to a much lesser extent, of the serotonin transporter can be transported into the cell by.

function

The serotonin transporter is responsible for the transport of serotonin from the extracellular space into the intracellular space. In the nervous system , the transporter takes over serotonin from the synaptic cleft and stops the action of serotonin. The exchange of serotonin between the enterochromaffin cells and the thrombocytes is also mediated via the serotonin transporter. In addition, the serotonin transporter is important for the serotonylation of intracellular proteins and thus a possible effect of serotonin as a messenger substance within the cell.

Individual evidence

↑ TCDB : 2.A.22
↑ Androutsellis-Theotokis A, Goldberg NR, Ueda K, et al. : Characterization of a functional bacterial homologue of sodium-dependent neurotransmitter transporters . In: J. Biol. Chem. . 278, No. 15, April 2003, pp. 12703-12709. doi : 10.1074 / jbc.M206563200 . PMID 12569103 .
↑ Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR , Iwata S: Structure and mechanism of the lactose permease of Escherichia coli . In: Science . 301, No. 5633, August 2003, pp. 610-5. doi : 10.1126 / science.1088196 . PMID 12893935 .
↑ Huang Y, Lemieux MJ, Song J, Auer M, Wang DN: Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli . In: Science . 301, No. 5633, August 2003, pp. 616-20. doi : 10.1126 / science.1087619 . PMID 12893936 .
↑ Zhou Z, Zhen J, Karpowich NK, et al. : LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake . In: Science . 317, No. 5843, September 2007, pp. 1390-1393. doi : 10.1126 / science.1147614 . PMID 17690258 .
↑ Kilic F, Rudnick G: Oligomerization of serotonin transporter and its functional consequences . In: Proc. Natl. Acad. Sci. USA . 97, No. 7, March 2000, pp. 3106-11. doi : 10.1073 / pnas.060408997 . PMID 10716733 . PMC 16200 (free full text).
↑ Paulmann N, Grohmann M, Voigt JP, et al. : Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation . In: PLoS Biol . . 7, No. 10, October 2009, p. E1000229. doi : 10.1371 / journal.pbio.1000229 . PMID 19859528 . PMC 2760755 (free full text).