Characterisation of the zebrafish serotonin transporter functionally links TM10 to the ligand binding site.

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Characterisation of the zebrafish serotonin transporter functionally links TM10 to the ligand binding site. / Severinsen, Kasper; Müller, Heidi Kaastrup; Wiborg, Ove; Sinning, Steffen.

I: Journal of Neurochemistry, 2008.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{eeccfd00ef3c11dcb919000ea68e967b,
title = "Characterisation of the zebrafish serotonin transporter functionally links TM10 to the ligand binding site.",
abstract = "The selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) act by inhibiting presynaptic reuptake of serotonin (5-HT) leading to elevated synaptic 5-HT concentrations. However, despite extensive efforts little is known about the protein-ligand interactions of SERT and inhibitors. To identify domains and individual amino acids important for ligand binding, we cloned the serotonin transporter from zebrafish, Danio rerio, (drSERT) and compared its pharmacological profile to that of the human serotonin transporter (hSERT) with respect to inhibition of [(3)H]5-HT uptake and [(3)H]-escitalopram binding in transiently transfected human embryonic kidney cells; HEK-293-MSR. Residues responsible for altered affinities inhibitors were pinpointed by generating cross-species chimeras and subsequent point mutations by site directed mutagenesis. drSERT has a higher affinity towards compounds of the imipramine class, desipramine in particular, exhibiting a 35-fold increased affinity compared to hSERT. drSERT has a 15-30-fold lower affinity towards cocaine and cocaine analogues. The differences in ligand recognition are shown to be primarily caused by interspecies differences in TM10 and were tracked down to three residues (Ala(505), Leu(506) and Ile(507)). Udgivelsesdato: 2008-Feb-7",
author = "Kasper Severinsen and M{\"u}ller, {Heidi Kaastrup} and Ove Wiborg and Steffen Sinning",
year = "2008",
doi = "10.1111/j.1471-4159.2008.05285.x",
language = "English",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell Publishing Ltd.",

}

RIS

TY - JOUR

T1 - Characterisation of the zebrafish serotonin transporter functionally links TM10 to the ligand binding site.

AU - Severinsen, Kasper

AU - Müller, Heidi Kaastrup

AU - Wiborg, Ove

AU - Sinning, Steffen

PY - 2008

Y1 - 2008

N2 - The selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) act by inhibiting presynaptic reuptake of serotonin (5-HT) leading to elevated synaptic 5-HT concentrations. However, despite extensive efforts little is known about the protein-ligand interactions of SERT and inhibitors. To identify domains and individual amino acids important for ligand binding, we cloned the serotonin transporter from zebrafish, Danio rerio, (drSERT) and compared its pharmacological profile to that of the human serotonin transporter (hSERT) with respect to inhibition of [(3)H]5-HT uptake and [(3)H]-escitalopram binding in transiently transfected human embryonic kidney cells; HEK-293-MSR. Residues responsible for altered affinities inhibitors were pinpointed by generating cross-species chimeras and subsequent point mutations by site directed mutagenesis. drSERT has a higher affinity towards compounds of the imipramine class, desipramine in particular, exhibiting a 35-fold increased affinity compared to hSERT. drSERT has a 15-30-fold lower affinity towards cocaine and cocaine analogues. The differences in ligand recognition are shown to be primarily caused by interspecies differences in TM10 and were tracked down to three residues (Ala(505), Leu(506) and Ile(507)). Udgivelsesdato: 2008-Feb-7

AB - The selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) act by inhibiting presynaptic reuptake of serotonin (5-HT) leading to elevated synaptic 5-HT concentrations. However, despite extensive efforts little is known about the protein-ligand interactions of SERT and inhibitors. To identify domains and individual amino acids important for ligand binding, we cloned the serotonin transporter from zebrafish, Danio rerio, (drSERT) and compared its pharmacological profile to that of the human serotonin transporter (hSERT) with respect to inhibition of [(3)H]5-HT uptake and [(3)H]-escitalopram binding in transiently transfected human embryonic kidney cells; HEK-293-MSR. Residues responsible for altered affinities inhibitors were pinpointed by generating cross-species chimeras and subsequent point mutations by site directed mutagenesis. drSERT has a higher affinity towards compounds of the imipramine class, desipramine in particular, exhibiting a 35-fold increased affinity compared to hSERT. drSERT has a 15-30-fold lower affinity towards cocaine and cocaine analogues. The differences in ligand recognition are shown to be primarily caused by interspecies differences in TM10 and were tracked down to three residues (Ala(505), Leu(506) and Ile(507)). Udgivelsesdato: 2008-Feb-7

U2 - 10.1111/j.1471-4159.2008.05285.x

DO - 10.1111/j.1471-4159.2008.05285.x

M3 - Journal article

C2 - 18266934

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

ER -