Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Interaction of antidepressants with the serotonin and norepinephrine transporters : mutational studies of the S1 substrate binding pocket. / Sørensen, Lena; Andersen, Jacob; Thomsen, Mette; Hansen, Stinna M.R.; Zhao, Xiaobei; Sandelin, Albin Gustav; Strømgaard, Kristian; Kristensen, Anders S.

In: The Journal of Biological Chemistry, Vol. 287, No. 52, 2012, p. 43694-43707.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Sørensen, L, Andersen, J, Thomsen, M, Hansen, SMR, Zhao, X, Sandelin, AG, Strømgaard, K & Kristensen, AS 2012, 'Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket', The Journal of Biological Chemistry, vol. 287, no. 52, pp. 43694-43707. https://doi.org/10.1074/jbc.M112.342212

APA

Sørensen, L., Andersen, J., Thomsen, M., Hansen, S. M. R., Zhao, X., Sandelin, A. G., Strømgaard, K., & Kristensen, A. S. (2012). Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket. The Journal of Biological Chemistry, 287(52), 43694-43707. https://doi.org/10.1074/jbc.M112.342212

Vancouver

Sørensen L, Andersen J, Thomsen M, Hansen SMR, Zhao X, Sandelin AG et al. Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket. The Journal of Biological Chemistry. 2012;287(52):43694-43707. https://doi.org/10.1074/jbc.M112.342212

Author

Sørensen, Lena ; Andersen, Jacob ; Thomsen, Mette ; Hansen, Stinna M.R. ; Zhao, Xiaobei ; Sandelin, Albin Gustav ; Strømgaard, Kristian ; Kristensen, Anders S. / Interaction of antidepressants with the serotonin and norepinephrine transporters : mutational studies of the S1 substrate binding pocket. In: The Journal of Biological Chemistry. 2012 ; Vol. 287, No. 52. pp. 43694-43707.

Bibtex

@article{e1caaed1b07640e69db349d37b44a28a,
title = "Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket",
abstract = "The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis for SERT/NET selectivity. Mutational analyses have suggested that a central substrate binding site (denoted the S1 pocket) also harbors an inhibitor binding site. In this study, we determine the effect of mutating six key S1 residues in human SERT (hSERT) and NET (hNET) on the potency of 15 prototypical SERT/NET inhibitors belonging to different drug classes. Analysis of the resulting drug sensitivity profiles provides novel information on drug binding modes in hSERT and hNET and identifies specific S1 residues as important molecular determinants for inhibitor potency and hSERT/hNET selectivity.",
keywords = "Animals, Antidepressive Agents, Binding Sites, COS Cells, Cercopithecus aethiops, Humans, Molecular Dynamics Simulation, Mutation, Norepinephrine Plasma Membrane Transport Proteins, Peptide Mapping, Protein Binding, Serotonin Plasma Membrane Transport Proteins",
author = "Lena S{\o}rensen and Jacob Andersen and Mette Thomsen and Hansen, {Stinna M.R.} and Xiaobei Zhao and Sandelin, {Albin Gustav} and Kristian Str{\o}mgaard and Kristensen, {Anders S}",
year = "2012",
doi = "10.1074/jbc.M112.342212",
language = "English",
volume = "287",
pages = "43694--43707",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "52",

}

RIS

TY - JOUR

T1 - Interaction of antidepressants with the serotonin and norepinephrine transporters

T2 - mutational studies of the S1 substrate binding pocket

AU - Sørensen, Lena

AU - Andersen, Jacob

AU - Thomsen, Mette

AU - Hansen, Stinna M.R.

AU - Zhao, Xiaobei

AU - Sandelin, Albin Gustav

AU - Strømgaard, Kristian

AU - Kristensen, Anders S

PY - 2012

Y1 - 2012

N2 - The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis for SERT/NET selectivity. Mutational analyses have suggested that a central substrate binding site (denoted the S1 pocket) also harbors an inhibitor binding site. In this study, we determine the effect of mutating six key S1 residues in human SERT (hSERT) and NET (hNET) on the potency of 15 prototypical SERT/NET inhibitors belonging to different drug classes. Analysis of the resulting drug sensitivity profiles provides novel information on drug binding modes in hSERT and hNET and identifies specific S1 residues as important molecular determinants for inhibitor potency and hSERT/hNET selectivity.

AB - The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis for SERT/NET selectivity. Mutational analyses have suggested that a central substrate binding site (denoted the S1 pocket) also harbors an inhibitor binding site. In this study, we determine the effect of mutating six key S1 residues in human SERT (hSERT) and NET (hNET) on the potency of 15 prototypical SERT/NET inhibitors belonging to different drug classes. Analysis of the resulting drug sensitivity profiles provides novel information on drug binding modes in hSERT and hNET and identifies specific S1 residues as important molecular determinants for inhibitor potency and hSERT/hNET selectivity.

KW - Animals

KW - Antidepressive Agents

KW - Binding Sites

KW - COS Cells

KW - Cercopithecus aethiops

KW - Humans

KW - Molecular Dynamics Simulation

KW - Mutation

KW - Norepinephrine Plasma Membrane Transport Proteins

KW - Peptide Mapping

KW - Protein Binding

KW - Serotonin Plasma Membrane Transport Proteins

U2 - 10.1074/jbc.M112.342212

DO - 10.1074/jbc.M112.342212

M3 - Journal article

C2 - 23086945

VL - 287

SP - 43694

EP - 43707

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 52

ER -

ID: 108150998