Serotonin Transporter: Difference between revisions

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The 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.<ref>PMID:8929413</ref> 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.<ref>DOI:10.1038/nn1944</ref> Massive genetic analysis of autistic patients reveals that the S allele is present significantly more in patients with [[Autism]] than without.<ref>PMID:16103890</ref> 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.<ref>PMID:15749252</ref> These elevated concentrations of serotonin also explain why [[Pharmaceutical Drugs|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.<ref>PMID:17677845</ref> 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.<ref>DOI:10.1038/448871a</ref> See also [[Atypical antipsychotics]].

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Tricyclic 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, <scene name='Serotonin_Transporter/Chlomipramine/1'>clomipramine</scene>, developed by Novartis, inhibits SERTs with remarkable efficacy. [[Clomipramine]] binds at the <scene name='Serotonin_Transporter/Chlomipramine_top/1'>entry way of the serotonin pore</scene> It forms a <scene name='Serotonin_Transporter/Chlomipramine_bound/1'>number of interactions</scene> which hold the molecule in place, completely occluding the pore. One particularly unique interaction involves a <scene name='Serotonin_Transporter/Chlomipramine_bound/2'>clomipramine-Arg-Phe</scene> 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 [[Clomipramine]] inhibits reuptake. <scene name='Serotonin_Transporter/Chlomipramine_top/2'>Clomipramine binds to the pore</scene>, but also, the closed pore conformation is stabilized by also <scene name='Serotonin_Transporter/Bound_sub/1'>binding its native ligand</scene>, 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 <scene name='Serotonin_Transporter/Bound_sub/2'>stabilized by a number of interactions</scene>.  Typically, a second leucine would likely bind in the clomipramine binding pocket, resulting in leucine release in the presynaptic space.<ref>PMID:17687333</ref>.  Another novel SSRI is [[Duloxetine]].

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;SSRIs are a second generation of very powerful antidepressants used to treat depression, anxiety disorders, and recently symptoms of [[autism]] by preventing <scene name='Serotonin_Transporter/Sert_remake/1'>SERT function</scene> ([[3gwu]]). Two well-known SSRIs, [[Sertraline]] (Zoloft) and [[fluoxetine]] (Prozac) bind in nearly the <scene name='Serotonin_Transporter/Sert_remake_bound/1'>same location as clomipramine </scene>. They are stabilized by a <scene name='Serotonin_Transporter/Bound_sertraline/1'>number of interactions</scene> 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 <scene name='Serotonin_Transporter/Hbd/1'>halogen binding pocket</scene> (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 <scene name='Serotonin_Transporter/Hbd_sub/1'>binding the substrate</scene>. The binding of Fluoxetine is <scene name='Serotonin_Transporter/Hbd_sub_flu/1'>nearly identical</scene> ([[3gwv]]) involving nearly all of the same residues.<ref>PMID:19430461</ref> Overall, it is clear the SSRI binds the <scene name='Serotonin_Transporter/Hbd_sub_fluo/1'>SERT in a conformation</scene> which does not allow entry of other substrates, thus preventing release and reuptake of other Serotonin molecules.