Organic Cation Transporters in Psychiatric Disorders
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Norepinephrine transporter
Reuptake
Synaptic cleft
Neurotransmitter transporter
Norepinephrine transporter
Reuptake
Synaptic cleft
Neurotransmitter transporter
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Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1-3; hOCT1-3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.
Norepinephrine transporter
Neurotransmitter transporter
Reuptake
Solute carrier family
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Norepinephrine transporter
Synaptic cleft
Reuptake
Tricyclic
Serotonin Uptake Inhibitors
Neurotransmitter transporter
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Neurotransmitter transporters are responsible for terminating signal transmission. hSERT (the human serotonin transporter) is the plasma membrane Na+/Cl--dependent transporter which is responsible for uptake of serotonin from the synaptic cleft. A previous study has shown that deleting the C-terminus of SERT impaired transporter activity and compromised its delivery to the plasma membrane) [1]. However, this study did not provide a mechanistic explanation. Alanine-scanning mutagenesis strategy was used in order to delineate which part of the C-terminus of SERT was required for folding of the protein. Pairs of alanine substitutions by site-directed mutagenesis have been produced and we are currently in the process of testing the effect of these mutations on the functional properties and the cellular localization of SERT. The preliminary data show that the mutation in P601G602-AA and R607I608-AA (Sec24 binding site) causes intracellular retention and abolishes uptake and binding.
Neurotransmitter transporter
Alanine
Alanine scanning
Synaptic cleft
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神経終末から放出されたノルエピネフリン（NE），ドパミン（DA）およびセロトニン（5-HT）は，それぞれに固有の細胞膜トランスポーター（NET，DAT，SERT）によりシナプス間隙から速やかに除去されて神経伝達が終息される．さらにこれらのモノアミンはシナプス小胞トランスポーター（VMAT）によりシナプス小胞内に輸送·貯蔵され再利用される．NET，DAT，SERTはNa+，Cl−依存性神経伝達物質トランスポーター遺伝子ファミリーに，VMATはH+依存性トランスポーター遺伝子ファミリーに属する．また選択的RNAスプライシングにより生じるアイソフォームが存在するものもある．NET，DAT，SERTは細胞膜を12回貫通し，細胞内にN末端とC末端が存在する分子構造を有すると予想される．近年，トランスポーターの発現は種々の調節機構により誘導性に制御されていると考えられるようになった．例えば，kinase/phosphataseの活性化によりその輸送活性あるいは発現が修飾され，トランスポータータンパク質あるいは相互作用するタンパク質のリン酸化による調節が考えられている．また，トランスポーターの発現は神経伝達物質それ自身の輸送活性に応じて調節されることやアンフェタミンなどの輸送基質あるいはコカインなどの取り込み阻害薬による薬物性にも調節されることが示唆されている．NET，DAT，SERTは抗うつ薬を始め種々の薬物の標的分子であることから，うつ病を始めとする様々な中枢神経疾患との関わりが調べられてきた．近年，遺伝子の解析からもその関連性が示唆されてきている．これまで抗うつ薬は必ずしも理論に基づき開発されたものばかりではなかったが，これらトランスポーターのcDNAを用いた発現系により，これまで検証できなかった多くの問題が分子レベルで詳細に検討されるようになった．その結果，多くの精神作用薬のプロフィールが明らかになったばかりでなく，より優れた，理論的に裏打ちされた多様な化学構造の新規治療薬の開発が可能となった．
Norepinephrine transporter
Neurotransmitter transporter
Vesicular monoamine transporter
Reuptake
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Presynaptic membrane serotonin transporters(SERT) and norepinephrine transporter(NET),which are important neurotransmitter transporters,are responsible for reuptake of released serotonin(5-HT) and norepinephrine(NE),respectively.The major function of these transporters is to terminate monoamine transmission by mediating uptake of neurotransmitters from extracellular space into neurons and glial cells.Drugs that inhibit the activity of monoamine transporters produce increased neurotransmitter levels in the synaptic cleft,leading to their therapeutic use in depression.As SERT and NET are pharmacological targets for most antidepressants,understanding about the molecular pharmacology of these transporters,including their localization and function,molecular structure and regulation,as well as drug binding sites and mechanism of action,is important to new antidepressant development.
Reuptake
Norepinephrine transporter
Neurotransmitter transporter
Synaptic cleft
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Neurotransmitter transporter
Norepinephrine transporter
Synaptic cleft
Reuptake
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Serotonin transporter (SERT) catalyzes reuptake of the neurotransmitter serotonin (5-HT) and is a target for antidepressant drugs and psychostimulants. It is a member of a large family of neurotransmitter and amino acid transporters. A recent study using site-directed cysteine modification identified a helical region of the transporter with high accessibility to the cytoplasm. Subsequently, the high resolution structure of LeuT, a prokaryotic homologue, showed that the residues corresponding to this helical region are part of the fifth transmembrane domain. The accessibility of these positions is now shown to depend on conformational changes corresponding to interconversion of SERT between two forms that face the extracellular medium and the cytoplasm, respectively. Binding of the extracellular inhibitor cocaine decreased accessibility at these positions, whereas 5-HT, the transported substrate, increased it. The effect of 5-HT required the simultaneous presence of Na+ and Cl-, which are transported into the cell together (symported) with 5-HT. In light of the LeuT structure, these results begin to define the pathway through which 5-HT diffuses between its binding site and the cytoplasm. They also confirm a prediction of the alternating access model for transport, namely, that all symported substrates must bind together before translocation.
Neurotransmitter transporter
Reuptake
Synaptic cleft
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Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
Desipramine
Reuptake
Norepinephrine transporter
Neurotransmitter transporter
Synaptic cleft
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Abstract Before this study, the human norepinephrine transporter (hNET) was the only member of the biogenic amine neurotransmitter transporter family that had not been demonstrated to be a functional homo‐oligomer. Here, using two forms of the transporter, I155C and hNET‐myc, with distinct antigenicity and inhibitor sensitivity, we demonstrated that hNET exists as a homo‐oligomer. hNET I155C is a functional mutant and is sensitive to inactivation by the sulfhydryl reagent [2‐(trimethylammonium)ethyl]methanethiosulfonate, while hNET‐myc is resistant to inactivation by this reagent. Coimmunoprecipitation of these two forms demonstrated that a physical interaction exists between norepinephrine transporter monomers. Further characterization of this physical interaction has revealed that the activity of norepinephrine transporters depends on interactions between monomers. Because norepinephrine transporters and serotonin transporters are the only two members of the neurotransmitter transporter family endogenously expressed in the cell membrane of the same cells, placental syncytiotrophoblasts, we tested the ability of norepinephrine transporters and serotonin transporters to associate and function in a hetero‐oligomeric form. Similarly, coexpression of hNET‐myc with serotonin transporter‐FLAG showed a physical interaction in coimmunoprecipitation assays. However, coexpression of serotonin and norepinephrine transporters did not sensitize norepinephrine transporter activity to inhibition by citalopram, a selective serotonin transport inhibitor. Thus, the norepinephrine transporter–serotonin transporter physical association did not produce functional consequences. Based on this, we propose that the transporters for biogenic amine neurotransmitters interact functionally in homo‐ but not hetero‐oligomeric forms.
Norepinephrine transporter
Neurotransmitter transporter
Biogenic amine
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