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Reuptake

Reuptake is the process by which neurotransmitters released into the synaptic cleft are rapidly reabsorbed into the presynaptic neuron or surrounding glial cells, primarily through specialized transporter proteins, to terminate their signaling action and enable recycling for future release.^[1] This mechanism is essential for regulating synaptic transmission, preventing overstimulation of postsynaptic receptors, and maintaining neurotransmitter homeostasis in the brain.^[2] The reuptake process typically involves sodium-dependent transporters embedded in the presynaptic membrane that co-transport the neurotransmitter back into the neuron along with ions such as sodium and chloride, powered by the electrochemical gradient established by the sodium-potassium pump.^[3] For monoamine neurotransmitters like dopamine, norepinephrine, and serotonin, specific transporters—known as the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), respectively—facilitate this reabsorption, ensuring efficient clearance from the synapse within milliseconds.^[4] In the case of excitatory amino acids like glutamate, reuptake is predominantly handled by glial cells via excitatory amino acid transporters (EAATs), where the neurotransmitter is converted to glutamine before being shuttled back to presynaptic neurons.^[2] Inhibitory neurotransmitters such as GABA and glycine are similarly cleared by dedicated transporters into either presynaptic terminals or glial cells, underscoring the diversity of reuptake systems across neurotransmitter types.^[5] Dysregulation of reuptake plays a critical role in various neurological and psychiatric disorders, as impaired clearance can lead to prolonged synaptic signaling and altered neural circuit function.^[6] Pharmacologically, reuptake inhibition is a cornerstone of treatments for conditions like depression and anxiety; for instance, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine bind to SERT to block serotonin reuptake, thereby increasing its availability in the synapse and enhancing serotonergic transmission.^[7] Similarly, drugs targeting DAT or NET, like bupropion, are used for disorders involving dopamine or norepinephrine imbalances, highlighting reuptake's therapeutic significance while also raising concerns about side effects from excessive neurotransmitter accumulation.^[8]

Fundamentals

Definition and Process

Reuptake is the process by which neurotransmitters released into the synaptic cleft are reabsorbed primarily by presynaptic neurons or surrounding glial cells through specific membrane transporters, thereby terminating their signaling action and regulating extracellular concentrations.^[9] This mechanism ensures precise control of synaptic transmission by rapidly clearing neurotransmitters after they have diffused across the cleft and interacted with postsynaptic receptors.^[10] The basic process begins with the exocytotic release of neurotransmitters from presynaptic vesicles into the synaptic cleft upon neuronal depolarization.^[11] These molecules then bind to and activate receptors on the postsynaptic neuron, eliciting a response, before diffusing within the cleft.^[2] Subsequently, specialized transporter proteins, such as those in the solute carrier family 6 (SLC6), facilitate the energy-dependent uptake of the neurotransmitters back into the presynaptic terminal, often co-transporting sodium ions to leverage the electrochemical gradient established by the Na+/K+-ATPase pump.^[10] Once internalized, the neurotransmitters are either repackaged into synaptic vesicles for reuse or enzymatically degraded within the neuron.^[12] This process primarily involves monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, as well as amino acid neurotransmitters like GABA and glutamate.^[9] For instance, serotonin reuptake is mediated by the serotonin transporter (SERT), while glutamate uptake occurs via excitatory amino acid transporters (EAATs).^[10] The transporters responsible for reuptake belong to conserved solute carrier families, with SLC6 members exhibiting evolutionary conservation across metazoans, including invertebrates like Drosophila and cnidarians, where analogous systems regulate amine and amino acid transport.^[13] Similar solute transport mechanisms, though not synaptic reuptake per se, are present in plants via homologous carrier proteins, underscoring the ancient origins of these molecular processes.^[14]

Biological Significance

Reuptake is essential for synaptic homeostasis, as it rapidly removes neurotransmitters from the synaptic cleft following their release, thereby terminating the postsynaptic signal and enabling precise temporal control of neurotransmission.^[15] This process ensures that neural signaling is transient and regulated, preventing indefinite activation of receptors and allowing synapses to recover for subsequent action potentials.^[16] Without efficient reuptake, synaptic transmission would lack the fidelity required for coordinated neural activity across brain circuits. In excitatory neurotransmitter systems, such as those involving glutamate, reuptake critically prevents excitotoxicity by limiting prolonged exposure of neurons to high extracellular concentrations of the transmitter.^[17] High-affinity transporters, particularly EAAT2 in astrocytes, clear synaptic glutamate to maintain submicromolar levels, averting calcium overload and subsequent neuronal damage or death.^[18] Impaired reuptake, as observed in conditions like amyotrophic lateral sclerosis, elevates glutamate and exacerbates excitotoxic pathways.^[17] Reuptake also promotes energy efficiency in neuronal function by recycling neurotransmitters back into presynaptic terminals or glial cells, reducing the metabolic cost of de novo synthesis.^[19] This recycling mechanism repackages transmitters into synaptic vesicles for reuse, conserving biosynthetic resources like amino acids and ATP-dependent transport processes.^[20] Such efficiency is vital in high-demand neural environments, where continuous transmitter production would otherwise strain cellular energy budgets. Dysregulation of reuptake can result in chronic neurotransmitter imbalances, contributing to psychiatric conditions; for instance, reduced serotonin transporter availability in regions like the midbrain is associated with major depressive disorder.^[21] Similarly, inhibition of dopamine reuptake by substances like cocaine prolongs extracellular dopamine in the nucleus accumbens, reinforcing reward pathways and fostering addiction through enhanced synaptic plasticity and compulsive drug-seeking.^[22] These disruptions highlight reuptake's role in maintaining balanced neurotransmission across systems like serotonergic and dopaminergic pathways.

Molecular Basis

Transporter Proteins

Transporter proteins responsible for reuptake primarily belong to the solute carrier (SLC) superfamily, with the sodium-dependent neurotransmitter transporters forming key families such as SLC6 for monoamines and SLC1 for glutamate.^[23]^[24] These proteins function as secondary active transporters, harnessing electrochemical gradients of ions to drive the uptake of neurotransmitters from the synaptic cleft into presynaptic neurons or glial cells against their concentration gradients.^[23]^[25] The SLC6 family, also known as the neurotransmitter-sodium symporter (NSS) family, includes transporters for monoamine neurotransmitters like serotonin, dopamine, and norepinephrine, as well as for inhibitory transmitters such as GABA and glycine.^[23] These transporters couple the influx of one or two sodium ions (Na⁺) and one chloride ion (Cl⁻) with the transport of the neurotransmitter substrate, utilizing the Na⁺/K⁺-ATPase-generated gradients for energy.^[23] In contrast, the SLC1 family comprises high-affinity glutamate transporters, termed excitatory amino acid transporters (EAATs), which co-transport three Na⁺ ions and one proton (H⁺) with glutamate while counter-transporting one potassium ion (K⁺), thereby maintaining low extracellular glutamate levels to prevent excitotoxicity.^[24]^[25] Key examples from the SLC6 family include the serotonin transporter (SERT, encoded by SLC6A4 on chromosome 17q11.2), which mediates serotonin reuptake; the dopamine transporter (DAT, encoded by SLC6A3 on chromosome 5p15.3), responsible for dopamine clearance; and the norepinephrine transporter (NET, encoded by SLC6A2 on chromosome 16q12.2), which handles norepinephrine reuptake.^[26]^[27] These genes produce proteins with multiple isoforms arising from alternative splicing, influencing expression and function in various tissues.^[23] For glutamate, the SLC1 family includes EAAT1 (SLC1A3) and EAAT2 (SLC1A2), predominantly expressed in astrocytes.^[24] In addition to plasma membrane transporters, vesicular monoamine transporters (VMATs) from the SLC18 family play a crucial role in intraneuronal storage by sequestering monoamines into synaptic vesicles after reuptake.^[28] VMAT1 (SLC18A1 on chromosome 8p21.3) is mainly found in peripheral neuroendocrine cells, while VMAT2 (SLC18A2 on chromosome 10q25.3) predominates in central monoaminergic neurons; both operate via proton (H⁺) antiport driven by vesicular acidification.^[28]^[29] These transporters exhibit structural variations that support their ion-coupling mechanisms, as explored in subsequent analyses of protein conformations.

Protein Structure

Reuptake transporters, primarily members of the solute carrier 6 (SLC6) family, exhibit a conserved overall architecture characterized by 12 transmembrane domains (TMDs) arranged in a bundle that spans the plasma membrane. These TMDs form two bundles of five helices each (TMD1-5 and TMD6-10) related by a pseudo-twofold symmetry axis lying parallel to the membrane plane, with TMD11 and TMD12 contributing to regulatory elements at the periphery. Extracellular loops (ELs), such as EL2 and EL4, line the solvent-exposed vestibule above the central substrate-binding site, while intracellular loops (ILs), including IL1 and IL5, help seal the cytoplasmic side. This inverted repeat topology creates a central cavity for ion and substrate coordination, as resolved in high-resolution structures of human homologs like the serotonin transporter (SERT) and dopamine transporter (DAT).^[30]^[31] Key structural motifs in these transporters facilitate dimerization and regulatory modifications. Leucine zipper-like sequences, consisting of heptad repeats of leucine residues, promote oligomerization, particularly through interactions involving TMD2 and TMD11, enabling stable dimer formation essential for proper trafficking to the cell surface without directly impacting transport kinetics. Additionally, intracellular phosphorylation sites, such as threonine 53 in DAT, serve as regulatory hotspots; phosphorylation here modulates transporter activity and substrate efflux in response to signaling cascades like protein kinase C activation. These motifs are embedded within the TMDs and termini, allowing dynamic responses to cellular cues.^[32]^[33] Conformational changes underpin the alternating access mechanism, transitioning from an outward-open state—where the extracellular vestibule is accessible for substrate and sodium binding—to an inward-open state for cytoplasmic release. Cryo-EM and X-ray structures capture these states: for instance, the 2016 X-ray structure of human SERT bound to antidepressants reveals an outward-open conformation with the central site occluded from the cytoplasm, while cryo-EM structures of human DAT from 2024 and 2025 show similar outward-facing features stabilized by inhibitors, as well as additional states bound to substrate dopamine.^[30]^[31]^[34] These transitions involve rigid-body movements of the helical bundles, with unwinding in TMD1 and TMD6 facilitating ion coordination and gate rearrangements.^[30]^[31] Structural variations between species highlight evolutionary adaptations in SLC6 transporters. Bacterial homologs like LeuT from Aquifex aeolicus share the core 12-TMD fold but possess short N- and C-termini (approximately 10 residues each), lacking the extended termini (>60 residues) in human counterparts that enable advanced regulation, such as phosphorylation-mediated interactions between the N-terminus and IL4. Human transporters also feature additional glycosylation sites on extracellular loops and more elaborate intracellular latches, like the helical CT domains in DAT, which stabilize gates and support eukaryotic-specific functions beyond basic symport. LeuT thus serves as a minimalist model, with its occluded state structure providing foundational insights into the conserved core.^[35]^[36]

Mechanisms

Normal Reuptake Mechanism

The normal reuptake mechanism of neurotransmitters operates through a secondary active transport process mediated by specific transporter proteins, following Michaelis-Menten kinetics that describe the binding, translocation, and dissociation steps. In this model, the transporter binds the extracellular neurotransmitter substrate with a characteristic affinity, quantified by the Michaelis constant (Km), which represents the substrate concentration at half-maximal transport velocity. For the dopamine transporter (DAT), the Km for dopamine is approximately 0.5-1 μM, reflecting high affinity under physiological conditions and enabling efficient clearance of synaptic dopamine concentrations typically in the nanomolar to low micromolar range.^[31] Similarly, the serotonin transporter (SERT) exhibits a Km for serotonin around 0.5 μM, while the norepinephrine transporter (NET) has a Km for norepinephrine of about 0.3 μM, illustrating substrate-specific affinities across monoamine systems.^[37] These kinetic parameters ensure rapid reuptake to terminate neurotransmission, with translocation occurring via conformational changes in the transporter protein. The energy for reuptake is coupled to the electrochemical gradient of sodium and chloride ions, established by the Na+/K+-ATPase, through a symport mechanism where ion influx drives the antiport of the neurotransmitter into the neuron. The stoichiometry varies among transporters: DAT cotransports 2 Na+ and 1 Cl- with one dopamine molecule, NET cotransports 1 Na+ and 1 Cl- with one norepinephrine molecule, and SERT cotransports 1 Na+, 1 Cl-, with countertransport of 1 K+ per serotonin molecule; these generate sufficient driving force to concentrate the neurotransmitter intracellularly against its gradient.^[38] This ion-substrate coupling yields a net inward current and powers the transport cycle without direct ATP hydrolysis at the transporter itself, achieving transport rates of approximately 1 molecule per second per transporter under optimal conditions.^[3] The transport cycle adheres to the alternating access model, progressing through distinct phases: the empty carrier adopts an outward-facing conformation accessible to the extracellular space; the neurotransmitter and co-ions bind to the central site, inducing a conformational flip to an inward-facing state via rigid-body movements of transmembrane domains; the substrate dissociates into the cytoplasm, followed by ion release; and the empty carrier returns to the outward-facing conformation, often facilitated by counter-transport of K+ ions in some systems to reset the transporter.^[39] This cyclic process, driven by the ion gradients, maintains low extracellular neurotransmitter levels and recycles substrates for repackaging into vesicles. The conformational flips are enabled by the structural architecture of the transporters, as detailed in analyses of their protein domains.^[39] Regulation of the reuptake rate occurs through post-translational modifications and environmental factors to fine-tune synaptic transmission. Phosphorylation by kinases such as protein kinase C (PKC) modulates transporter activity, often reducing uptake velocity (Vmax) by promoting endocytosis or altering conformational dynamics, as seen in PKC-mediated phosphorylation of serine residues on DAT that decreases dopamine clearance.^[40] Temperature influences kinetics by affecting membrane fluidity and enzyme-like rates of conformational changes, with reuptake efficiency peaking at physiological body temperature (around 37°C) and declining at lower temperatures due to slowed translocation.^[41] Likewise, pH modulates binding affinity and ion coupling, with acidic extracellular pH impairing uptake by protonating key residues, while physiological pH (7.2-7.4) optimizes transport across systems like SERT and DAT.^[42]

Inhibition Mechanisms

Reuptake inhibition occurs through pharmacological agents or pathological conditions that disrupt the normal cycling of neurotransmitter transporters, preventing the clearance of neurotransmitters from the synaptic cleft. Competitive inhibitors, such as cocaine, bind directly to the central substrate-binding pocket (S1 site) of transporters like the dopamine transporter (DAT), occluding the binding of dopamine and stabilizing the outward-open conformation to block uptake.^[31] This mechanism is exemplified by cocaine's interaction with residues in subsites A, B, and C within the S1 pocket of human DAT, with a Ki of approximately 200-700 nM.^[43] Similarly, selective serotonin reuptake inhibitors (SSRIs) like S-citalopram engage both the central S1 site and an extracellular vestibule (S2 site) on the serotonin transporter (SERT), locking it in the outward-open state and preventing the conformational shift necessary for serotonin translocation.^[44] Non-competitive inhibitors act at allosteric sites distinct from the substrate pocket, modulating transporter function without directly competing for neurotransmitter binding. For instance, modafinil inhibits DAT through an atypical mechanism, likely involving an allosteric site that favors inward-facing conformations or alters gating, though its affinity is relatively low compared to classical blockers.^[45] Compounds like MRS7292 demonstrate non-competitive inhibition of DAT by binding approximately 13 Å above the central site in the extracellular vestibule, inducing a fit that displaces transmembrane helices TM1b and TM6a, thereby slowing ligand dissociation and inhibiting transport.^[31] These allosteric interactions, often involving extracellular loops (e.g., EL4), restrict the transporter's ability to transition to inward-facing states required for reuptake.^[46] Pathological inhibition can arise from genetic mutations that impair transporter function or from toxins that reverse transport direction. Loss-of-function mutations in SLC6A4 (encoding SERT), such as disruptive variants identified in affective disorders, reduce serotonin uptake by altering protein folding or trafficking, effectively mimicking pharmacological blockade.^[47] The SERT Ala56 variant (A56), while primarily a gain-of-function mutation increasing baseline uptake and associated with anxiety disorders, can lead to dysregulated inhibition under certain conditions due to enhanced constitutive phosphorylation that stabilizes high-activity states.^[48] Toxins like amphetamines act as substrates for DAT and SERT, promoting reverse transport by entering the cell, dissipating ion gradients (e.g., via Na+/H+ exchange), and facilitating neurotransmitter efflux rather than influx, thereby elevating synaptic levels.^[49] This reversal mechanism depends on the transporter's inward-facing conformation and is independent of classical competitive binding.^[50] These inhibition mechanisms extend the dwell time of neurotransmitters in the synapse, prolonging signaling from typical half-lives of seconds to minutes or longer, which amplifies postsynaptic receptor activation.^[10] For example, DAT blockade by competitive inhibitors like cocaine increases extracellular dopamine persistence, altering reward pathways.^[31] Overall, such disruptions highlight the transporters' vulnerability to molecular interventions at distinct sites, influencing synaptic homeostasis.

Physiological Roles

Neurotransmitter Systems

Reuptake plays a critical role in regulating neurotransmitter levels across various human neural pathways, with specific transporters tailored to each system to maintain synaptic homeostasis and signaling precision. In monoaminergic systems, reuptake primarily occurs via sodium-dependent transporters that terminate neurotransmission by recycling transmitters back into presynaptic neurons. Amino acid systems, such as glutamatergic and GABAergic, employ distinct transporters for rapid clearance to prevent overstimulation or imbalance. In the serotonergic system, the serotonin transporter (SERT), also known as SLC6A4, facilitates reuptake primarily in projections originating from the raphe nuclei in the brainstem, which innervate widespread brain regions including the cortex and limbic areas. This process regulates extracellular serotonin levels, contributing to mood stabilization by controlling the duration and intensity of serotonergic signaling in these circuits. SERT's activity ensures efficient termination of serotonin release, allowing for precise modulation of emotional processing. The dopaminergic system relies on the dopamine transporter (DAT, or SLC6A3) for reuptake in key pathways such as the nigrostriatal tract, which projects from the substantia nigra to the dorsal striatum, and the mesolimbic pathway, extending from the ventral tegmental area to the nucleus accumbens. DAT-mediated reuptake in the nigrostriatal pathway supports fine-tuned control of motor functions by rapidly clearing dopamine from synapses involved in movement initiation and coordination. In the mesolimbic system, DAT regulates dopamine dynamics essential for reward processing, motivation, and reinforcement learning, preventing excessive accumulation that could disrupt behavioral adaptability. For the noradrenergic system, the norepinephrine transporter (NET, or SLC6A2) handles reuptake in projections from the locus coeruleus, a brainstem nucleus that distributes norepinephrine throughout the cortex, hippocampus, and other regions. NET's role in these circuits modulates arousal states by terminating noradrenergic signaling, thereby influencing vigilance, attention, and the integration of sensory information. Additionally, NET contributes to stress responses by regulating norepinephrine availability in sympathetic and central pathways, ensuring balanced autonomic and cognitive reactions. In glutamatergic and GABAergic systems, reuptake is mediated by excitatory amino acid transporters (EAATs) for glutamate and GABA transporters (GATs) for GABA, both of which are crucial for maintaining excitatory-inhibitory balance. EAATs, particularly EAAT2 (GLT-1), predominantly expressed on astrocytes, rapidly clear glutamate from synapses to prevent excitotoxicity, where excessive glutamate could lead to neuronal damage from overactivation of receptors like NMDA. GATs, including GAT-1 and GAT-3, reuptake GABA mainly via neuronal and glial mechanisms, sustaining inhibitory tone and averting hyperexcitability that might precipitate seizures by dysregulating circuit inhibition. Regional distribution of these transporters varies significantly, reflecting specialized functions. DAT expression is notably high in the basal ganglia, particularly the striatum, aligning with its role in motor and reward circuits. In contrast, SERT is abundant not only in serotonergic brain regions but also peripherally in the gut's enteric nervous system, where it regulates gastrointestinal motility, and in platelets, facilitating serotonin storage for hemostasis.

Neuroprotective Functions

Reuptake mechanisms contribute significantly to neuroprotection by regulating extracellular neurotransmitter levels, thereby mitigating excitotoxic and oxidative damage to neurons. In glutamatergic systems, excitatory amino acid transporters (EAATs), particularly EAAT2 (also known as GLT-1), rapidly clear excess glutamate from the synaptic cleft, preventing its accumulation that could overactivate ionotropic receptors such as NMDA. This overactivation triggers excessive calcium influx, activating downstream pathways like calpain and caspase cascades that culminate in neuronal apoptosis and cell death. By maintaining low extracellular glutamate concentrations, EAAT-mediated reuptake averts such excitotoxic cascades, preserving neuronal integrity during physiological signaling or pathological stress.^[51] In monoaminergic neurotransmission, reuptake transporters such as the dopamine transporter (DAT) and serotonin transporter (SERT) provide protection against oxidative stress by limiting extracellular exposure of these catechols to auto-oxidation. For example, extracellular dopamine is prone to non-enzymatic oxidation, forming dopamine quinones that generate reactive oxygen species (ROS) and modify proteins, leading to mitochondrial dysfunction and neuronal toxicity. Efficient DAT-mediated reuptake internalizes dopamine for vesicular repackaging or enzymatic metabolism, thereby reducing the formation of these harmful quinones and associated oxidative damage in dopaminergic neurons. Similarly, SERT facilitates serotonin clearance, modulating oxidative pathways in serotonergic systems, though the protective effects are most pronounced in dopamine-rich regions vulnerable to stress.^[52] Following ischemic events like stroke, reuptake transporters exhibit adaptive upregulation to enhance clearance of excess neurotransmitters and promote recovery. In cerebral ischemia, glutamate transporters such as GLT-1 are upregulated in astrocytes, accelerating the removal of released glutamate and mitigating prolonged excitotoxicity in the penumbra region. This response helps restore ionic balance and limits secondary neuronal injury from sustained receptor overstimulation. Pharmacological induction of such upregulation, for instance via ceftriaxone, has demonstrated neuroprotective effects by bolstering reuptake capacity during the acute phase.^[53]^[54] Aging impairs reuptake efficiency, exacerbating neurodegeneration through dysregulated neurotransmitter homeostasis. Age-related decline in DAT density and function, observed as approximately 5-7% per decade loss in striatal binding, leads to elevated extracellular dopamine levels, promoting oxidative stress and contributing to dopaminergic neuron loss in Parkinson's disease. This progressive reduction in transporter expression correlates with mitochondrial dysfunction and protein aggregation, accelerating vulnerability in aging brains. Similar declines in other transporters, like SERT, compound these effects across monoaminergic systems, underscoring reuptake's role in age-dependent neuroprotection.^[55]^[56]

Clinical and Pathological Aspects

Role in Disorders

Dysregulation of reuptake mechanisms, particularly involving the serotonin transporter (SERT), has been implicated in major depressive disorder (MDD). Studies using positron emission tomography (PET) imaging have consistently shown reduced SERT binding in key brain regions such as the midbrain and thalamus in individuals with MDD compared to healthy controls, suggesting lower transporter density contributes to impaired serotonin clearance and synaptic accumulation.^[57] A meta-analysis of in vivo and postmortem studies further confirms this reduction in limbic regions, supporting SERT dysfunction as a biomarker for depression vulnerability.^[58] In attention-deficit/hyperactivity disorder (ADHD), polymorphisms in the dopamine transporter (DAT) gene (SLC6A3) are associated with altered transporter function and increased risk. The 3'-untranslated region variable number tandem repeat (VNTR) polymorphism, particularly the 10-repeat allele, has been linked to higher DAT expression and binding in the striatum, correlating with ADHD symptoms like hyperactivity and impulsivity in genetic association studies.^[59] Haplotype analyses in family-based cohorts replicate this association, indicating that DAT variants influence dopamine reuptake efficiency and contribute to the disorder's dopaminergic dysregulation.^[60] Neurologically, DAT loss is a hallmark of Parkinson's disease (PD), where degeneration of nigrostriatal dopaminergic neurons leads to substantial reductions in striatal DAT binding. Imaging studies reveal approximately 30-50% striatal DAT loss in early PD, progressing with disease severity and correlating with motor symptom onset due to diminished dopamine reuptake capacity.^[61] Similarly, downregulation of the excitatory amino acid transporter 2 (EAAT2), the primary glutamate reuptake protein in astrocytes, is observed in amyotrophic lateral sclerosis (ALS), resulting in elevated extracellular glutamate and excitotoxic motor neuron damage.^[62] In epilepsy, particularly temporal lobe epilepsy, aberrant EAAT2 mRNA splicing and reduced protein expression in the hippocampus impair glutamate clearance, exacerbating seizure susceptibility.^[63] Chronic cocaine use disrupts DAT-mediated dopamine reuptake, leading to addiction through pharmacodynamic tolerance. Repeated cocaine exposure inhibits DAT, causing initial synaptic dopamine surges, but prolonged administration induces DAT downregulation in striatal regions, reducing transporter density and blunting cocaine's acute effects, which drives escalated intake to achieve euphoria.^[64] This tolerance mechanism involves lasting alterations in DAT phosphorylation and function, as evidenced in self-administration models.^[65] Genetic variations in the SLC6A4 gene, which encodes SERT, further link reuptake to anxiety disorders. The short (S) allele of the 5-HTTLPR promoter polymorphism is associated with reduced SERT expression and increased lifetime risk of panic disorder, as shown in large community-based studies post-2000.^[66] This allele moderates environmental stressors, amplifying anxiety symptoms in childhood adversity contexts through impaired serotonin reuptake.^[67]

Therapeutic Targeting

Therapeutic targeting of reuptake processes primarily involves pharmacological agents that inhibit neurotransmitter transporters to enhance synaptic concentrations of monoamines, thereby alleviating symptoms in various psychiatric and neurological disorders. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, selectively block the serotonin transporter (SERT) to increase serotonin availability in the synaptic cleft, forming the cornerstone of treatment for major depressive disorder and anxiety disorders.^[7] Fluoxetine, the first SSRI approved by the U.S. Food and Drug Administration in December 1987, exemplifies this class by potently inhibiting SERT with minimal impact on other transporters, leading to sustained elevation of extracellular serotonin levels.^[68] Common side effects of SSRIs include gastrointestinal disturbances and sexual dysfunction, but a more severe risk is serotonin syndrome, a potentially life-threatening condition arising from excessive serotonergic activity, characterized by symptoms such as hyperthermia, agitation, and autonomic instability.^[69] Serotonin-norepinephrine reuptake inhibitors (SNRIs), like venlafaxine, extend this approach by inhibiting both SERT and the norepinephrine transporter (NET), thereby boosting levels of both neurotransmitters to address depression with comorbid pain or fatigue.^[70] Venlafaxine demonstrates dose-dependent inhibition, with higher doses enhancing NET blockade alongside SERT effects, which contributes to its efficacy in treatment-resistant depression.^[71] While SNRIs share SSRI side effects, they may additionally elevate blood pressure due to noradrenergic enhancement, necessitating monitoring in hypertensive patients.^[70] For dopamine-related conditions, inhibitors of the dopamine transporter (DAT) have proven effective. Methylphenidate, a DAT blocker, increases synaptic dopamine in prefrontal and striatal regions, improving attention and executive function in attention-deficit/hyperactivity disorder (ADHD), where it is a first-line treatment.^[72] Bupropion, another DAT inhibitor with weaker NET affinity, aids smoking cessation by attenuating nicotine cravings and withdrawal through enhanced dopaminergic signaling in reward pathways.^[73] Emerging therapies aim to refine reuptake modulation for greater specificity and reduced adverse effects. Allosteric modulators of SERT and DAT, explored in post-2020 structural studies, bind to non-competitive sites on transporters to fine-tune reuptake without fully occluding the substrate-binding pocket, potentially minimizing toxicity while enhancing therapeutic windows.^[74] Gene therapy approaches target congenital transporter defects, such as dopamine transporter deficiency syndrome (DTDS), by delivering functional DAT genes via adeno-associated viral vectors to restore transporter expression in affected neurons, showing preclinical promise in improving motor and cognitive deficits.^[75] As of 2023, the AAV2-based gene therapy BGT-DTDS received FDA Rare Pediatric Disease Designation and Orphan Drug Designations from FDA and EMA, with a Phase 1/2/3 clinical trial application planned for submission in 2024, advancing toward clinical evaluation.^[76] Despite these advances, challenges persist in reuptake inhibitor development, including off-target effects that can lead to unintended serotonergic or dopaminergic disruptions, such as autonomic instability or exacerbated psychiatric symptoms.^[77] The lengthy timeline from discovery to approval, exemplified by the nearly 15 years between fluoxetine's initial synthesis in 1972 and its 1987 market entry, underscores regulatory hurdles and the need for extensive safety profiling.^[78]

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Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38) : 10:117,241,114 ... genes, Slc18a1 and Slc18a2, to chromosomes 8 and 19 by linkage analysis.Missing: VMAT | Show results with:VMAT
[30]
X-ray structures and mechanism of the human serotonin transporter
Here we report x-ray crystallographic structures of human SERT at 3.15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine.
[31]
Structure of the human dopamine transporter and mechanisms of ...
Aug 7, 2024 · The human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn 2+ are without a high-resolution structural context.
[32]
Oligomer formation by Na+–Cl−-coupled neurotransmitter ...
Thus, by analogy with soluble proteins, a leucine zipper-like structure may exist that forms the interaction domain in transmembrane domain proteins.
[33]
The SLC6 transporters: perspectives on structure, functions ...
The most extensively studied members of the human SLC6 family are neurotransmitter reuptake transporters, many of which are important drug targets for the ...
[34]
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters - Nature
### Summary of LeuT Structure from https://www.nature.com/articles/nature03978
[35]
How structural elements evolving from bacterial to human SLC6 ...
Mar 14, 2018 · To learn how the structural elements added in evolution enable mechanisms of the eukaryotic transporters in ways not shared with their bacterial ...
[36]
Mechanism for alternating access in neurotransmitter transporters
Jul 29, 2008 · In the alternating access model, a central binding site for substrates is connected to the two sides of the membrane by permeation pathways ...Missing: phases | Show results with:phases
[37]
Phosphorylation Mechanisms in Dopamine Transporter Regulation
Our current evidence indicates that PKC and MAPK domain phosphorylation affect uptake kinetics, likely in different directions, and that both domains regulate ...
[38]
Effect of Temperature on Dopamine Transporter Function and ...
Temperature has been found to markedly influence METH-induced DA neurotoxicity. In particular, hyperthermia consistently exacerbates METH-induced DA ...
[39]
H+ Permeation and pH Regulation at a Mammalian Serotonin ...
Apr 1, 1997 · In addition, pH affects other conducting states of rat serotonin transporter. Acidic pH potentiates the 5-HT-induced, transport-associated ...
[40]
The mechanism of a high-affinity allosteric inhibitor of the serotonin ...
Mar 20, 2020 · SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In ...
[41]
Unlocking the Potential of High-Quality Dopamine Transporter ...
Mar 11, 2024 · Thus, cocaine stabilizes DAT in an outward-facing conformation, whereas atypical inhibitors, such as modafinil and JHW007, favor inward-facing ...
[42]
Frontiers | Structure and Gating Dynamics of Na+/Cl
Sep 5, 2019 · This review seeks to address structural dynamics of neurotransmitter transporters at the extracellular and intracellular gates and the effect of inhibitors on ...Missing: SLC1 glutamate<|control11|><|separator|>
[43]
[PDF] Disruptive mutations in the serotonin transporter associate - medRxiv
Aug 29, 2023 · Here we investigate rare genetic variants in SLC6A4 in a sample of patients with. 14 affective disorders, uniquely selected for a highly ...
[44]
Role of Phosphorylation of Serotonin and Norepinephrine ... - MDPI
It is postulated that elevated SERT constitutive phosphorylation, caused by the Ala56 mutation, might prevent this variant from switching between high and low ...
[45]
Amphetamine induces dopamine efflux through a dopamine ... - PNAS
We report that AMPH causes DAT-mediated DA efflux by two independent mechanisms: (i) a slow process consistent with an exchange mechanism and (ii) a process ...
[46]
A closer look at amphetamine induced reverse transport and ... - NIH
Given that AMPH serves as a substrate for DAT, its transport into the cell increases the number of transporters in the inward facing conformation, and thus ...
[47]
Role of glutamate excitotoxicity and glutamate transporter EAAT2 in ...
In this review we discuss targeting EAAT2, the predominant glutamate transporter in the CNS, as a promising approach for developing therapies for epilepsy.Missing: GATs | Show results with:GATs
[48]
Dopamine Quinone Formation and Protein Modification Associated ...
Feb 15, 1999 · Methamphetamine-induced toxicity has been shown to require striatal dopamine and to involve mechanisms associated with oxidative stress.Missing: DAT SERT
[49]
The Role of the Dopamine Transporter in Dopamine‐Induced DNA ...
The neurotransmitter dopamine causes DNA damage, oxidative stress and is involved in the pathology of neurological diseases.Missing: SERT neuroprotection
[50]
Pharmacological Induction of Ischemic Tolerance by Glutamate ...
Nov 22, 2006 · In this study, we investigated the neuroprotective effect of GLT-1 upregulation during cerebral ischemia. CTX treatment was found to upregulate ...
[51]
Activation of Glutamate Transporter-1 (GLT-1) Confers Sex ...
Jan 8, 2021 · During ischemic stroke, glutamate is released, reuptake processes are impaired, and glutamate promotes excitotoxic neuronal death. Astrocytic ...
[52]
Age-Related Decline in Dopamine Transporters: Analysis of Striatal ...
Neuroimaging studies have documented an age-related decline in striatal dopamine transporters (DATs) as a marker of dopaminergic neurodegeneration.
[53]
The Relationship Between the Striatal Dopaminergic Neuronal and ...
Feb 27, 2020 · The aim of this study was to elucidate the association among age-related changes in the striatal dopamine transporter (DAT) and cognitive function in healthy ...
[54]
Lower Brain Serotonin Transporter Binding in Major Depressive ...
These findings confirm prior observations of lower SERT binding in depression, and suggest that low SERT binding may represent a putative biomarker of ...
[55]
The serotonin transporter in depression: Meta-analysis of in vivo and ...
Nov 1, 2015 · Conclusions: The results indicate that serotonin transporter availability in depressed patients is reduced in key regions of the limbic system.<|separator|>
[56]
Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine ...
Our findings suggest that an ADHD risk polymorphism (3′-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans. Keywords: ...
[57]
Haplotype study of three polymorphisms at the dopamine transporter ...
Our study of 102 nuclear families with an ADHD proband replicates and extends the findings of the previous studies of an association of DAT1 and ADHD.
[58]
Dopamine Transporter Imaging in Parkinson Disease - NIH
The decline rates of DAT binding become small gradually from the early stage to the advanced stage in PD patients. The first comparative study between DAT ...Missing: aging | Show results with:aging
[59]
EAAT2 and the molecular signature of amyotrophic lateral sclerosis
The neuronal damage caused by excessive stimulation, known as excitotoxicity, has been implicated in a variety of acute and chronic conditions, including ALS, ...
[60]
Alternative splicing of glutamate transporter EAAT2 RNA in ...
Rationale: Altered expression of glutamate transporter EAAT2 protein has been reported in the hippocampus of patients with temporal lobe epilepsy (TLE).
[61]
Cocaine Self-Administration Produces Pharmacodynamic Tolerance
Mar 7, 2012 · In addition to the acute pharmacological effects of cocaine, chronic administration has been shown to modify presynaptic DA terminal function.
[62]
Altered dopamine transporter function and phosphorylation ...
These results show that chronic cocaine self-administration leads to lasting, regionally specific alterations in striatal DA uptake and DAT-Ser phosphorylation.
[63]
The Serotonin Transporter Gene Polymorphism (SLC6A4) and Risk ...
Aug 12, 2020 · The human serotonin transporter (SERT) is encoded by a single gene (SLC6A4) located on the long arm of chromosome 17 (17q11-17q12). The most ...
[64]
SLC6A4 gene variants moderate associations between childhood ...
Feb 15, 2024 · The SLC6A4 short/short allele amplifies risk of anxiety‐related mental illness when children experience food insecurity. The gene–environment ...
[65]
The Story of Prozac: A Landmark Drug in Psychiatry
Mar 1, 2020 · In December 1987, fluoxetine (which had now been branded as Prozac) received FDA approval for the treatment of major depression. Within a few ...
[66]
Serotonin Syndrome - StatPearls - NCBI Bookshelf - NIH
Mar 2, 2024 · Serotonin syndrome may occur as a consequence of therapeutic medication use, illicit drug use, or intentional overdose. Multiple substances may ...
[67]
Venlafaxine - StatPearls - NCBI Bookshelf
Venlafaxine increases serotonin and norepinephrine levels in the central nervous system by blocking transport proteins and inhibiting their reuptake at the ...Continuing Education Activity · Indications · Mechanism of Action · Administration
[68]
Estimates of Serotonin and Norepinephrine Transporter Inhibition in ...
Apr 16, 2008 · Paroxetine and venlafaxine are potent serotonin transporter (SERT) antagonists and weaker norepinephrine transporter (NET) antagonists.
[69]
Ventral striatum supports Methylphenidate therapeutic effects on ...
Jan 20, 2020 · Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD).
[70]
Bupropion: Uses, Interactions, Mechanism of Action | DrugBank Online
When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which ...Identification · Pharmacology · Categories · References<|separator|>
[71]
Allosteric modulation of serotonin and dopamine transporters
We present here a comparative study of the structural dynamics and ligand-binding properties of two MATs, dopamine transporter (DAT) and serotonin transporter ...Missing: therapies post-
[72]
Gene therapy restores dopamine transporter expression ... - Science
May 19, 2021 · Here, Ng et al. developed a gene therapy for DTDS using patient-derived induced pluripotent stem cell (iPSC) and a mouse model.
[73]
Implications of Off‐Target Serotoninergic Drug Activity: An Analysis ...
The striking overlap of autonomic and mental status symptoms (e.g., blood pressure instability, tachycardia, tachypnea, tremor, mydriasis, confusion, and ...
[74]
The Discovery of Fluoxetine Hydrochloride (Prozac) - Nature
Aug 24, 2005 · In the meantime, Astra Pharmaceuticals, with help from the Carlsson group, had introduced the SSRI zimelidine (Zelmid) in Europe in 1982 for the ...