Serotonin Transporter: Difference between revisions
David Canner (talk | contribs) New page: Serotonin transporter’’’s’’’ (‘’’SERTs’’’) are integral membrane proteins that transport serotonin from synaptic spaces into presynaptic neurons. Serotonin is a... |
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[[Serotonin | <StructureSection load='1dq8' size='500' side='right' caption='Structure of HMG-CoA reductase (PDB entry [[1dq8]])' scene=''> | ||
[[Serotonin Transporter]]'''s''' ('''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.<ref>PMID:10405096</ref> 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 Autism==== | ====SERTs Involvement in OCD and Autism==== | ||
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.(RESSLER) Massive genetic analysis of autistic patients reveals that the S allele is present significantly more in patients with [[Autism]] than without. (DEVLIN) 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.(SCOTT) 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 (both benzodiazepines), 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.(INSEL) 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.(HYMAN) | 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.(RESSLER) Massive genetic analysis of autistic patients reveals that the S allele is present significantly more in patients with [[Autism]] than without. (DEVLIN) 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.(SCOTT) 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 (both benzodiazepines), 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.(INSEL) 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.(HYMAN) | ||
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SSRIs are a second generation of very powerful antidepressants used to treat depression, anxiety disorders, and recently symptoms of [[autism]] by preventing **SERT function**. Two well-known SSRIs, Sertraline (Zoloft) and fluoxetine (Prozac) bind in nearly the **same location as chlomipramine SERTRALINE**. They are stabilized by a **number of interactions** 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 halogen binding pocket (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 **binding the substrate** Leucine. The binding of Fluoxetine is** nearly identical** involving nearly all of the same residues. | SSRIs are a second generation of very powerful antidepressants used to treat depression, anxiety disorders, and recently symptoms of [[autism]] by preventing **SERT function**. Two well-known SSRIs, Sertraline (Zoloft) and fluoxetine (Prozac) bind in nearly the **same location as chlomipramine SERTRALINE**. They are stabilized by a **number of interactions** 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 halogen binding pocket (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 **binding the substrate** Leucine. The binding of Fluoxetine is** nearly identical** involving nearly all of the same residues. | ||
Overall, the discovery of SSRIs was a profound step forward in treating severe disorders which at one point were nearly completely debilitating. | Overall, the discovery of SSRIs was a profound step forward in treating severe disorders which at one point were nearly completely debilitating. | ||
</StructureSection> | |||
==References== | |||
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