2.A.22.1.1
Serotonin (5-hydroxytryptamine; 5 HT):Na⁺:Cl^- symporter, SERT-A  It also transports amphetamines; blocked by cocaine and tricyclic antidepressants such as Prozac; interacts directly with the secretory carrier-associated membrane protein-2 (SCAMP2; O15127) to regulate the subcellular distribution (Muller et al., 2006). The 3 D structure is known ()PDB 5I6X), and it uses an alternating sites mechanism with all 3 substrates bound (Zhang and Rudnick, 2006).  Molecular determinants for antidepressants in the human serotonin and norepinephrine A transporters have been identified (Andersen et al., 2011). A conserved asparagine residue in transmembrane segment 1 (TMS1) of the serotonin transporter dictates chloride-coupled neurotransmitter transport (Henry et al., 2011). The formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation (Gabrielsen et al., 2012). Methylation of the SLC6A4 gene promoter controls depression in men by an epigenetic mechanism (Devlin et al., 2010).  The 5HT K_m is 0.4 micromolar (Banovic et al. 2010).  Regulated allosterically by ATM7 which stabilizes the outward-facing conformation of SERT (Kortagere et al. 2013).  Functional and regulatory mechanisms involving the N- and C-terminal hydrophilic domains have been considered (Fenollar-Ferrer et al. 2014).  The range of substrates bound and transported has been predicted (Kaufmann et al. 2009).  TMS3 may function in substrate and antagonist recognition (Walline et al. 2008).  The 3-d x-ray structures with antidepressants bound have been solved, leading to mechanistic predictions; antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between TMSs 1, 3, 6, 8 and 10, directly blocking serotonin binding (Coleman et al. 2016).  Na⁺ and cocaine stabilize outward-open conformations of SERT and decrease phosphorylation while agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increase phosphorylation. The opposing effects of the inhibitors, cocaine and ibogaine, were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na⁺ and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively (Zhang et al. 2016).  SERT is regulated by multiple molecular mechanisms including its physical interaction with intracellular proteins including the ASCT2 (alanine-serine-cysteine-threonine 2; TC# 2.A.23.3.2), co-expressed with SERT in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane (Seyer et al. 2016).  SERT transports substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) (Sealover et al. 2016).  A naturally occurring mutation, I425V, associated with obsessive-compulsive disorder and other neuropsychiatric disorders, activates hSERT and eliminates stimulation via the cyclicGMP-dependent pathway (Zhang et al. 2007).  The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters. In SERT, Glu394 plays a role in MDMA recognition (Sealover et al. 2016). Intestinal dysbiosis may upregulate SERT expression and contribute to the development of chronic constipation (Cao et al. 2017). Cryo-EM structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations have been solved (Coleman et al. 2019). Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMSs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TMS 1a and the partial unwinding of TMS 5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm, thus defining the structural rearrangements that occur from the outward-open to inward-open conformations. SERT and cholecytokinin (CCK) seem to be involved in the pathogenesis of Irrritable Bowl Syndrome (IBS-D) by regulating the brain-gut axis and affecting visceral sensitivity (Qin et al. 2020). Altered SERT function leads to several neurological diseases including depression, anxiety, mood disorders, and attention deficit hyperactivity disorders (ADHD) (Szöllősi and Stockner 2021). The structure and dynamics of the two sodium binding sites indicate that sodium binding is accompanied by an induced-fit mechanism that leads to new conformations (Szöllősi and Stockner 2021). Occlusion of the  serotonin transporter is mediated by serotonin-induced conformational changes in the bundle domain (Gradisch et al. 2022). A structural rearrangement of the SERT intracellular gate is induced by Thr276 phosphorylation (Chan et al. 2022). Na⁺/Cl^--dependent neurotransmitter transporters form oligomers. A leucine heptad repeat in TMS2 and a glycophorin-like motif in TMS6 may stabilize the oligomer (Just et al. 2004). Oligomerization of hSERT involves at least two discontinuous interfaces to form an array-like structure containing multimers of dimers (Just et al. 2004). Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. A decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR; decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation (Castillero et al. 2023). Cocaine-regulated trafficking of dopamine transporters in cultured neurons has been revealed using a pH sensitive reporter (Saenz et al. 2023). Two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes (Nichols et al. 2023). Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region (Hu et al. 2012). Dehydroevodiamine has a dihedral angle of 3.71 degrees compared to 82.34 degrees for evodiamine. Dehydroevodiamine can more easily pass through a phospholipid bilayer than evodiamine because it has a more planar stereo-structure (Luo et al. 2023).  SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health (Pilkay et al. 2024).