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Serotonin Transporter and Reuptake
Transcript of Serotonin Transporter and Reuptake
5 - hydroxytryptamine
Monoamine inhibitory neurotransmitter
Derived from tryptophan
Connected to mood and emotion, appetite and sleep
Produced and stored in:
Located mainly in the brainstem
What is Serotonin?
Limbic system: connected by neural transmitter pathways. Plays a role in physiological changes, and behaviors
As a serotonin transporter, the protein encoded by the
is responsible for the reuptake of serotonin.
Polymorphism in 5-HTT
A Closer Look at 5-HTT and it's Relation to Behavior
Produced by neurons in the Raphe nuclei (brainstem)
Provide feedback to the suprachiasmatic nuclei (SCN), thus contributing in circadian rhythms
Extend process to release serotonin onto almost the entire brain as well as the spinal cord
Serotonin reuptake inhibitors are targeted in these nuclei
Notice the difference in caudal vs rostral nuclei
How other parts of the brain are affected
The precise structure of this protein has not been determined, but it is known to be located in the presynaptic cell membrane.
The activity and number of the serotonin transporter proteins determine the length of time that the chemical signal remains in the synapse
5-HTT transporter for its role in depression
Figure 2. Diagram of the action of Serotonin and the Serotonin Transporter. This diagram shows the neurotransmitter serotonin being released from the presynaptic cell and binding to the receptors on the postsynaptic cell. 5-HTT encodes the protein labeled "reuptake transporter." Image from http://psychclerk.bsd.uchicago.edu/lect_depression.html
Figure 1. Serotonin Pathways in the Brain. This image shows the areas in the brain in which serotonin is active. Image from: http://www.drugabuse.gov/pubs/teaching/teaching4/Teaching3.html
Serotonin pathway, specifically the serotonin transporter, are involved in mood control
•Multiple antidepressant medications
•Researchers study the 5-HTT transporter for its role in depression.
•Cite studies that associated the 5-HTT gene with anxiety in monkeys and mice. Later studies: presence of the short allele with human anxiety after exposure to disturbing images (Duenwald, 2003)
Other studies however do not produce conclusive evidence for the link between 5-HTT and depression and acknowledging that some studies found no association with the gene and depression.
Use these findings in practical applications – ability to predict depression
NY Times article states that even though the alleles of the 5-HTT gene are called “short” and “ long”, the protein that they produce is the same
Long allele just produces MORE of the protein
Article in Science explains the reasoning: the polymorphism doesn’t occur within the open reading frame of 5-HTT gene itself, but in the
5’ regulatory region.
The terms “short” and “long” refer to two different lengths of the sequences in the gene’s regulatory region.
Figure 3. Simplified Diagram of 5-HTT gene associated region polymorphism. This diagram shows the two alleles of the 5-HTT gene region. The transcription factor binding sites and actual translated region of the gene are identical, but the alleles differ in the 5' repeat (VNTR-Variable Number Tandem Repeat) region. Image idea from Glatz et. al., 2003.
The 44 bp deletion in the regulatory section of the 5-HTT "short" (s) allele occurs 1 kb
of the transcription initiation site of the gene (OMIM, 2003).
The polymorphism causes decreased gene expression and fewer serotonin transporters in the membrane of the cell. Thus, rate of reuptake of serotonin is reduced. This research tries to correlate this phenomenon with the development of depression. (Caspi et. al., 2003).
Conclusions: Can 5-HTT Be Used in Diagnosis
Useful correlation between the gene and phenotype of depression
• Speculation: clinical implications is premature
Science article stresses the importance of genetic factors
Demonstrated a useful correlation between the gene and phenotype of depression
•May not directly “cause” disease
•Moderate responses to environmental factors (Capsi, et. al. 2003)
Caspi A et. al. 2003. Influence of Life Stress on Depression: Moderation in the 5-HTT Gene. Science 301: 386-389.
Di Bella, D. et. al. 1996. Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE. Am J Med Genet. 67: 541-5.
Duenwald M. 2003. Gene is Linked to Susceptibility to Depression. The New York Times. July, 18 2003. <http://query.nytimes.com/gst/abstract.html?res=F00712FC3B580C7B8DDDAE0894DB404482> Accessed 2003 28 Aug.
Glatz, K et. al. 2003. Glucocorticoid-regulated human serotonin transporter (5-HTT) expression is modulated by the 5-HTT gene-promotor-linked polymorphic region. Journal of Neurochemistry 86: 1072-1078.