Academic journal article Alcoholism and Psychiatry Research

Serotonin Transporter Polymorphism in Relation to Depression

Academic journal article Alcoholism and Psychiatry Research

Serotonin Transporter Polymorphism in Relation to Depression

Article excerpt


Much has been written about serotonin, its physiology and effects through the course of time but we still cannot claim to know everything about this neurotransmitter. Serotonin is regarded as one of the most important factors in modern psychiatry and therefore is no wonder that many studies deal with serotonin in one way or another. Research regarding serotonin transporter is no exception and this article will try to pro vide a closer and more concise report of research conducted thus far.

5-hydroxytryptamine, or just serotonin, plays an important role in neurodevelopment and functioning of the brain. It is involved in regulation of a wide variety of functions and behaviors such as appetite, sleep, mood, motor activity, emotions and altered neuroendocrine function [1]. Serotonin functions as a short-range neurotransmitter, a paracrine neuronal modulator at a number of different receptors and as a long-range signaling modulator. Its effects are multiple and spread throughout the organism via plasma, platelet, neuroendocrine, gut, adrenal and other peripheral systems across many species [2].

The serotonin transporter (5-HTT) is a monoamine transporter protein with a crucial role in serotoninergic function. It terminates synaptic actions of 5-HT and transports it from synaptic spaces into presynaptic neurons, effectively recycling it into the neurotransmitter pool [3]. 5-HTT also has a major role in regulation of the homeostasis of spatial distribution and intensity of 5-HT signals with 5-HT receptors [4-6]. Serotonin transporter is encoded by the gene termed SLC6A4 that maps to chromosome 17q11.2. It is composed of 15 exons spanning about 40 kb. The sequence of the transcript predicts a protein comprised of 630 amino acids with 12 transmembrane domains. Alternative promoters, differential splicing involving exons 1A, B, and C, and 30-untranslated-region variability result in multiple mRNA species, as well as specific polymorphisms, that are likely to regulate gene expression SLC6A4 in humans. Best studied is the promoter region polymorphism, 5-HTTLPR, which together with two intrinsic single nucleotide polymorphisms (SNP's) [rs25531 and rs25532], all located upstream of the transcription start site, modulate the transcriptional activity of SLC6A4 [2,7-9]. Additional variants at the SLC6A4 locus include a functional variable number of tandem repeats (VNTR) polymorphism in intron 2 and a number of other coding region SNP's that change the structure or function of the transporter protein, such as I425V and G56A [2,8,1013]. Most of these SNP's are rare [7,14].

As mentioned, best studied polymorphisms of the serotonin system are linked with the 5-HTT gene-linked polymorphic region (5-HTTLPR), a repetitive element of varying length located in the promoter region of SLC6A4. It modulates the transcriptional activity of human 5-HTT. Alleles of the serotonin transporter polymorphism are most commonly composed of either fourteen (short or S allele) or sixteen (long or L allele) repeated elements which affect transporter expression and function [15]. However, other alleles have also been identified at low frequency, including 15-, 18-, 19-, 20-, and 22-repeat alleles, with various additional SNPs distinguishing some repeats [16]. More recently, 5-HTTLPR polymorphisms have been researched from a newer viewpoint. Specifically, an A/G nucleotide substitution in the L allele renders the 5-HTTLPR tri-allelic with the functional variants of the L allele designated as LA and LG [17]. Similar was observed for the S allele and it was subdivided into SA and SG18. It was observed that the A variant - LA produces high levels of mRNA and that the G variant - LG is equivalent to the S allele [7,19,20].

Other polymorphisms in this gene that have been reported include: functional VNTR polymorphism comprised of 9, 10, or 12 copies of a 16/17 bp element located in intron 2 of the serotonin transporter gene, termed Stin2 VNTR and a single nucleotide polymorphism (SNP) in the 30 untranslated region (UTR) [4,21-23]. …

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