Serotonin Transporter
From Proteopedia
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Revision as of 11:10, 20 March 2022
IntroductionSerotonin Transporters (SERTs) are integral membrane proteins that transport serotonin from synaptic spaces into presynaptic neurons. Serotonin is an important neurotransmitter which impacts a mammal’s perception of resource availability, regulates mood, and some cognitive functions like memory and learning. It is also converted into melatonin by Serotonin N-acetyltransferase to regulate sleep cycles. SERTs function by reuptaking serotonin in the synaptic cleft, effectively terminating the function of serotonin and halting neuronal transmission. Serotonin reuptake is a critical process to prevent overstimulation of nerves.[1] Inappropriately low levels of serotonin, either due to reduced production or overly active SERTs, can cause a number of psychiatric disorders. SERTs Involvement in OCD and AutismThe gene that encodes the SERTs is SLC6A4. The promoter region of SLC6A4 has two well-known polymorphisms aptly named “short” and “long” corresponding to the number of repeats in the 5-HTT-linked polymorphic region (HTTLPR). The short variation of this promoter leads to less transcription of the SERT gene SLC6A4.[2] Further, studies have found that the short allele of HTTLPR is associated with changes in the brain structure such as reduced grey matter in the perigeniculate region surrounding Cg25 and in the amygdala, areas important for emotional processing and mood regulation.[3] Massive genetic analysis of autistic patients reveals that the S allele is present significantly more in patients with Autism than without.[4] Since the presence of the short-HTTLPR promoter results in fewer SERTs being produced, and SERTs function by reuptaking and thus limiting serotonin-induced signal transduction, it is not unexpected that over 30% of autistic individuals, who more commonly have the short-HTTLPR allele, have elevated concentrations of serotonin.[5] These elevated concentrations of serotonin also explain why pharmaceutical therapeutics like selective serotonin reuptake inhibitors (SSRIs), including the well-known Zoloft and Prozac, have been shown to alleviate some symptoms of autism. The same is true for the well-known Obsessive-Compulsive disorder (OCD), patients of which suffer from intrusive mental tics resulting in repetitive rituals such as washing their hands obsessively often.[6] Although OCD is believed to be caused by aberrant functioning of glutamate responsive synapses, treatment with serotonin reuptake inhibitors helps treat symptoms of OCD possibly because serotonin modulates glutamate action, as validated by mouse models.[7] Structure of SERTsSERTs are members of the sodium-coupled transporter family. These proteins harness the pre-existing sodium gradients to catalyze the uptake of serotonin. Unfortunately, no high-resolution structure of a SERT has been solved. Instead a prokaryotic homolog of SERT, i.e. LeuT has been solved. LeuT shares significant sequence homology, especially for areas of the protein critical for function. The is dominated by alpha helices. Serotonin passes through a upon reuptake. the serotonin bound structure before releasing serotonin within the presynaptic neuron. Pharmaceutical ImplicationsTricyclic antidepressants (TCAs) were among the first antidepressants ever developed. Discovered in the 1950s, they are named after their unique structure which contains three rings. One of the best known TCAs, , developed by Novartis, inhibits SERTs with remarkable efficacy. Chlomipramine binds at the It forms a which hold the molecule in place, completely occluding the pore. One particularly unique interaction involves a sandwhich involving residues Arg 30 and Phe 253. As mentioned before, this structure is of LeuT and not a SERT, but the structures have significant homology. The structure reveals how Chlomipramine inhibits reuptake. , but also, the closed pore conformation is stabilized by also , which in this case is leucine, but in the case of a SERT, would be serotonin. The Leucine molecule is bound below the inhibitor and is . Typically, a second leucine would likely bind in the Chlomipramine binding pocket, resulting in leucine release in the presynaptic space.[8] SSRIs are a second generation of very powerful antidepressants used to treat depression, anxiety disorders, and recently symptoms of autism by preventing (3gwu). Two well-known SSRIs, Sertraline (Zoloft) and fluoxetine (Prozac) bind in nearly the . They are stabilized by a with the SERT structure. Interestingly, both of these second generation antidepressants contain halogenated subgroups which interact in very specific ways with the transporter structure. In the case of sertraline, the chlorine atoms on the phenyl ring insert into a pocket dubbed the (HBP). This pocket consists of residues Leu 25, Gly 26, Leu 29, Arg 30, Tyr 108, Ile 111, and Phe 253. Several of these residues, Leu 25, Gly 26, Tyr 108, and Phe 253 are also involved in . The binding of Fluoxetine is (3gwv) involving nearly all of the same residues.[9] Overall, it is clear the SSRI binds the which does not allow entry of other substrates, thus preventing release and reuptake of other Serotonin molecules. Overall, the discovery of SSRIs was a profound step forward in treating severe disorders which at one point were nearly completely debilitating. 3D structures of serotonin transporterUpdated on 20-March-2022
Page DevelopmentThis article was developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University. References
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