The medical benefit of 5-HT research

Jones, Brian; Blackburn, Thomas P.

doi:10.1016/s0091-3057(01)00745-6

Cited by 206 publications

(151 citation statements)

References 116 publications

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“…Interestingly, the ones with the strongest 5-HT receptor blocking activity tend to have the lowest extrapyramidal side effects (EPS) (Jones and Blackburn, 2002). 5-HT2A receptor antagonism may confer on antipsychotic drugs atypicality with relatively weaker D2 receptor antagonism (or partial D2 receptor agonism) because of the ability of 5-HT2A receptors to differentially modulate the activity of dopaminergic neurones depending on regions of the brain.…”

Section: Introductionmentioning

confidence: 99%

YKP1447, A Novel Potential Atypical Antipsychotic Agent

Dong

Heo

et al. 2009

Korean J Physiol Pharmacol

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(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10∼ 100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced head twitch (ED50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED50=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.

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Section: Introductionmentioning

confidence: 99%

YKP1447, A Novel Potential Atypical Antipsychotic Agent

Dong

Heo

et al. 2009

Korean J Physiol Pharmacol

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“…The biophysical properties of the 5-HT 3A and the 5-HT 3A/B receptors exhibit significant differences, with those of the heteromer more closely resembling those of the receptor characterized within the majority of mammalian systems (9)(10)(11)(12). Competitive antagonists of 5-HT 3 receptors are used clinically as antiemetics in cancer chemotherapy and in general anesthesia, although other applications are being explored (13). The two receptor subtypes are difficult to distinguish pharmacologically (14), although picrotoxin (15) and tubocurarine (7) are markedly less potent in blocking agonist-induced currents in the exogenously expressed heteromeric receptors.…”

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confidence: 99%

Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT₃receptors

Barrera

Herbert

Henderson

et al. 2005

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

111

104

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The 5-HT3 receptor is a cation-selective ligand-gated ion channel of the Cys-loop superfamily. The receptor is an important therapeutic target, with receptor antagonists being widely used as antiemetics in cancer therapy. The two known receptor subunits, A and B, form homomeric 5-HT 3A receptors and heteromeric 5-HT3A/B receptors. The heteromeric receptor has the higher single-channel conductance and more closely mimics the properties of the native receptor. We have used atomic force microscopy to study the architecture of 5-HT 3A and 5-HT3A/B receptors. We engineered different epitope tags onto the A-and B-subunits and imaged receptors that were doubly liganded by anti-epitope antibodies. We found that, for the 5-HT 3A/B receptor, the distribution of angles between antibodies against the A-subunit had a single peak at Ϸ144°, whereas the distribution for antibodies against the B-subunit had two peaks at Ϸ72°and 144°. Our results indicate that the subunit stoichiometry is 2A:3B and that the subunit arrangement around the receptor rosette is B-B-A-B-A. This arrangement may account for the difference between the agonist Hill coefficients and the single-channel conductances for the two types of receptor.ligand-gated ion channel ͉ receptor structure T he 5-HT 3 receptor is a member of the Cys-loop ligand-gated ion channel superfamily, together with the nicotinic acetylcholine receptor, the GABA A receptor, and the glycine receptor (1-3). Electron microscopy of the affinity purified 5-HT 3 receptor has shown that it contains five subunits arranged pseudosymmetrically around a cylinder of long axis 11 nm and external diameter 8 nm (4, 5). The vestibule of the channel, normally open to the cell exterior, is visible as an opening of diameter 2-3 nm. Two 5-HT 3 receptor subunits have been investigated in detail. The first to be cloned, 5-HT 3A (6), expresses as a functional homomer, whereas the second, 5-HT 3B , is unable to form functional channels alone but expresses robustly in the presence of the 5-HT 3A subunit (7). The genes for these two subunits are located in close proximity on chromosome 11, although additional putative 5-HT 3 receptor genes have been isolated on chromosome 3 (8). The biophysical properties of the 5-HT 3A and the 5-HT 3A/B receptors exhibit significant differences, with those of the heteromer more closely resembling those of the receptor characterized within the majority of mammalian systems (9-12). Competitive antagonists of 5-HT 3 receptors are used clinically as antiemetics in cancer chemotherapy and in general anesthesia, although other applications are being explored (13). The two receptor subtypes are difficult to distinguish pharmacologically (14), although picrotoxin (15) and tubocurarine (7) are markedly less potent in blocking agonist-induced currents in the exogenously expressed heteromeric receptors. Although there is some anatomical evidence that the homomeric receptor may be expressed alone in the rat (16, 17), current functional evidence suggests that it is the heteromer that is o...

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“…Amphetamine and its derivatives, including 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), interact with SERT, DAT, and NET as substrates (5,6). Inhibitors that prevent 5-HT reuptake into serotonergic neurons have been used to treat a variety of neuropsychiatric disorders, including affective disorder, anxiety disorder, obsessive-compulsive disorder, and autism (7)(8)(9). Furthermore, the incidence of some psychiatric disorders and the effectiveness of antidepressant drugs has been linked to polymorphisms in the promoter of the gene encoding SERT (10 -13).…”

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confidence: 99%

Cysteine-scanning Mutagenesis of Serotonin Transporter Intracellular Loop 2 Suggests an α-Helical Conformation

Zhang

Rudnick

2005

Journal of Biological Chemistry

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The serotonin transporter (SERT, 1 SLC6A4) is a presynaptic plasma membrane protein responsible for the reuptake of serotonin (5-hydroxytrypatamine, abbreviated 5-HT) after its release by neurons. It is a member of a large family of amine and amino acid transporters (SLC6, NSS) distributed throughout the prokaryotic and animal kingdoms. Together with norepinephrine and dopamine transporters (NET and DAT), SERT is part of a subgroup of transporters that mediate the transport of biogenic amine neurotransmitters by symport with Na ϩ and Cl Ϫ ions (1). SERT is of particular interest in neurobiology because it is the molecular target of several drugs of abuse and many therapeutic agents used to treat psychiatric disorders. Along with NET and DAT, SERT is inhibited by cocaine, and cocaine analogues bind to SERT with high affinity (2-4). Amphetamine and its derivatives, including 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), interact with SERT, DAT, and NET as substrates (5, 6). Inhibitors that prevent 5-HT reuptake into serotonergic neurons have been used to treat a variety of neuropsychiatric disorders, including affective disorder, anxiety disorder, obsessive-compulsive disorder, and autism (7-9). Furthermore, the incidence of some psychiatric disorders and the effectiveness of antidepressant drugs has been linked to polymorphisms in the promoter of the gene encoding SERT (10 -13).A naturally occurring mutation in human SERT, I425V, was found to be associated with obsessive-compulsive disorder and several other 5-HT-related disorders (14). Further investigation revealed that this mutation caused SERT to be in an activated state that is reached in the wild type through the action of cGMP-dependent protein kinase (15).Hydropathy analysis of SERT predicted 12 transmembrane (TM) domains connected by intracellular and extracellular loops (16,17). This analysis predicted that the second intracellular loop (IL2) was a short cytoplasmic loop containing nine residues connecting TM domains 4 and 5. Further analysis suggested that this loop contained consensus phosphorylation sites for cGMP-dependent protein kinase and protein kinase C (18). From the location of glycosylation sites in the second extracellular loop, the NH 2 and COOH termini were predicted to be cytoplasmic (19). Subsequent experiments using mutagenesis and chemical modification in intact cells and disrupted membranes have verified the overall topology (20, 21). However, the extent of most of the loops remains unknown, with the exception of extracellular loops 4 (22) and 5 (23).Previous studies of intracellular and extracellular loop residues by cysteine substitution have revealed changes in conformation of these loops in response to substrate and inhibitor binding (21,22,24,25). To further examine the structure of SERT IL2, we have studied IL2 by cysteine-scanning mutagenesis. The results reported here suggest that it is longer than predicted and contains an ␣-helical structure. EXPERIMENTAL PROCEDURESMutagenesis-Mutant transporters were gen...

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The medical benefit of 5-HT research

Cited by 206 publications

References 116 publications

YKP1447, A Novel Potential Atypical Antipsychotic Agent

YKP1447, A Novel Potential Atypical Antipsychotic Agent

Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT₃receptors

Cysteine-scanning Mutagenesis of Serotonin Transporter Intracellular Loop 2 Suggests an α-Helical Conformation

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The medical benefit of 5-HT research

Cited by 206 publications

References 116 publications

YKP1447, A Novel Potential Atypical Antipsychotic Agent

YKP1447, A Novel Potential Atypical Antipsychotic Agent

Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT3receptors

Cysteine-scanning Mutagenesis of Serotonin Transporter Intracellular Loop 2 Suggests an α-Helical Conformation

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Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT₃receptors