Serotonin transporters: Implications for antidepressant drug development

White, Kellie J.; Walline, Crystal C.; Barker, Eric L.

doi:10.1208/aapsj070242

Cited by 64 publications

(38 citation statements)

References 84 publications

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“…Functional deficiency in 5-HT signaling has been implicated in the pathophysiology of various depressive syndromes [2][3][4]. A major goal of antidepressant therapy is to restore 5-HT signaling by elevating extracellular 5-HT levels in the brain [4,5]. Consequently, genes involved in 5-HT clearance, such as the serotonin reuptake transporter (SERT) and the monoamine oxidases (MAOs), have long been considered as drug targets for the treatment of depression [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…A major goal of antidepressant therapy is to restore 5-HT signaling by elevating extracellular 5-HT levels in the brain [4,5]. Consequently, genes involved in 5-HT clearance, such as the serotonin reuptake transporter (SERT) and the monoamine oxidases (MAOs), have long been considered as drug targets for the treatment of depression [5,6]. For example, the widely used selective serotonin reuptake inhibitors (SSRIs) exert their pharmacological effects by specifically blocking SERT-mediated 5-HT reuptake.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain

Zhou

Engel

Wang

2007

Biochemical Pharmacology

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The high affinity serotonin transporter (SERT) constitutes the principal pathway for removal of serotonin (5-HT) from extracellular fluid of brain, but evidence indicates that other transporters may also be involved in this process. We recently reported the cloning of a novel plasma membrane monoamine transporter (PMAT), which is abundantly expressed in the human brain and avidly transports 5-HT (J Biol Chem 279(48): 2004) . In this study, we evaluated whether PMAT contributes to total human brain uptake of 5-HT using a hybrid depletion approach in Xenopus laevis oocytes. We also examined whether PMAT interacts with selective serotonin reuptake inhibitors (SSRIs) using MDCK cells stably expressing recombinant human PMAT. Microinjection of total human brain poly(A) + mRNA into oocytes elicited ~2.5-3 fold increase in 5-HT uptake. Prehybridization of poly(A) + mRNA with PMAT or SERT antisense oligonucleotides significantly reduced mRNA-induced 5-HT uptake. An additive inhibitory effect was observed when poly(A) + mRNA was co-hybridized with both PMAT and SERT antisense oligonucleotides. In contrast, mRNA-induced 5-HT uptake was not affected by pre-hybridization with sense oligonucleotides. These data suggest that functional transcripts of PMAT are present in the human brain, and the PMAT transporter may be significantly involved in brain uptake of 5-HT. All five tested SSRIs inhibited PMAT with IC 50 values ranging from 11-116 μM, which are much greater than clinically encountered concentrations, suggesting that PMAT activity is minimally affected by SSRI therapies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain

Zhou

Engel

Wang

2007

Biochemical Pharmacology

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“…The activity of serotonergic pathways is critically regulated by the reuptake of 5-HT via the plasma membrane serotonin transporter (SERT), a member of the Na ϩ /Cl Ϫ -dependent transporter family (SLC6) (1,2). SERT is of major pharmacological and clinical interest inasmuch as it represents the primary target of several widely prescribed antidepressants, including the selective [5-hydroxytryptamine (5-HT)] reuptake inhibitors, citalopram and paroxetine (2)(3)(4). Moreover, altered SERT expression or function has been suggested not only in depression, but also in anxious and obsessive-compulsive states, disorders that can likewise be improved by treatment with selective 5-HT reuptake inhibitors (4)(5)(6).…”

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confidence: 99%

Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity

Chanrion

Cour

Bertaso

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

161

145

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The spatiotemporal regulation of neurotransmitter transporters involves proteins that interact with their intracellular domains. Using a proteomic approach, we identified several proteins that interact with the C terminus of the serotonin transporter (SERT). These included neuronal nitric oxide synthase (nNOS), a PSD-95/ Disc large/ZO-1 (PDZ) domain-containing protein recruited by the atypical PDZ binding motif of SERT. Coexpression of nNOS with SERT in HEK293 cells decreased SERT cell surface localization and 5-hydroxytryptamine (5-HT) uptake. These effects were absent in cells transfected with SERT mutated in its PDZ motif to prevent physical association with nNOS, and 5-HT uptake was unaffected by activation or inhibition of nNOS enzymatic activity. 5-HT uptake into brain synaptosomes was increased in both nNOS-deficient and wild-type mice i.v. injected with a membrane-permeant peptidyl mimetic of SERT C terminus, which disrupted interaction between SERT and nNOS, suggesting that nNOS reduces SERT activity in vivo. Furthermore, treating cultured mesencephalic neurons with the mimetic peptide similarly increased 5-HT uptake. Reciprocally, indicating that 5-HT uptake stimulates nNOS activity, NO production was enhanced on exposure of cells cotransfected with nNOS and SERT to 5-HT. This effect was abolished by 5-HT uptake inhibitors and absent in cells expressing SERT mutated in its PDZ motif. In conclusion, physical association between nNOS and SERT provides a molecular substrate for their reciprocal functional modulation. In addition to showing that nNOS controls cell surface localization of SERT, these findings provide evidence for regulation of cellular signaling (NO production) by a substrate-carrying transporter.PDZ ͉ proteomic ͉ serotonin uptake S erotonin plays a major role in the regulation of mood, cognition, and motor behavior, and a disruption of serotonergic transmission is implicated in several pathophysiological states, including affective disorders. The activity of serotonergic pathways is critically regulated by the reuptake of 5-HT via the plasma membrane serotonin transporter (SERT), a member of the Na ϩ /Cl Ϫ -dependent transporter family (SLC6) (1, 2). SERT is of major pharmacological and clinical interest inasmuch as it represents the primary target of several widely prescribed antidepressants, including the selective [5-hydroxytryptamine (5-HT)] reuptake inhibitors, citalopram and paroxetine (2-4). Moreover, altered SERT expression or function has been suggested not only in depression, but also in anxious and obsessive-compulsive states, disorders that can likewise be improved by treatment with selective 5-HT reuptake inhibitors (4-6).Over the last 10 years, it has become evident that monoaminergic and other classes of plasma membrane transporters are not isolated proteins ''floating'' within the plasma membrane, but rather are components of protein complexes. These generally incorporate an oligomer (possibly formed of dimers) of the transporter that is physically associated with several i...

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“…They are also widely prescribed for treating various other mental disorders such as obsessive compulsive and social phobic disorders [7,8].…”

Section: Introductionmentioning

confidence: 99%

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

Oya

Choi

Kung

et al. 2007

Nuclear Medicine and Biology

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Two novel ligands with a 4′-substitution on the phenyl ring B of biphenylthiol: 5-chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine, 7, and 2-(2′-((dimethylamino) methyl)-4′-methoxyphenylthio)-5-iodobenzenamine, 8, were prepared and tested as potential serotonin transporter (SERT) imaging agents. The new ligands displayed extremely high binding affinities to SERT (K i = 0.22 ± 0.09 and 0.11 ± 0.04 nM, respectively), with very low binding affinities to dopamine and norepinephrine transporters (K i > 1, 000 nM). The corresponding [ 125 I]7 and [ 125 I] 8 were successfully prepared from the tri-n-butyltin derivatives. They showed good brain uptakes and prolonged retention after iv injection in rats (brain uptake was 1.77 and 0.98 %dose/g for [ 125 I] 7 and 0.92 and 0.29 %dose/g for [ 125 I]8 at 2 and 120 minutes, respectively). Significantly, [ 125 I]7 showed excellent uptake and prolonged retention in the hypothalamus, where the SERT concentration is the highest. The hypothalamus/cerebellum ratios (target to background ratios) were 4.24, 7.10, 8.24 and 12.6 at 2, 4, 6 and 12 hours, respectively. The hypothalamus/cerebellum ratios for [ 125 I]8 were 3.97, 5.57 and 5.06 at 1, 2 and 4 hours, respectively. Adding the 4′-iodo-group to the phenyl ring B of 7 appeared to reduce the rate of clearance from the brain, and the kinetics favored uptake and retention in the hypothalamus. The localization of [ 125 I]7 in the hypothalamus region in the brain of rats could be blocked by pretreatment with (+)McN5652, escitalopram and ADAM (2), all selective serotonin transporter ligands (at 2 mg/Kg dose, iv, 5 min pretreatment). Ex vivo autoradiograms of rat brain sections (at 4 hr after iv injection of [ 125 I]7) showed intense labeling in regions of the brain known to have high SERT density. The excellent selective uptake and retention in the hypothalamus region suggests that [ 123 I]7 is a potential lead compound for developing new imaging agents targeting SERT binding sites with single photon emission computed tomography (SPECT).

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Serotonin transporters: Implications for antidepressant drug development

Cited by 64 publications

References 84 publications

Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain

Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain

Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

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