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.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Lena
authors.initials: L
authors.lastname: Sørensen
authors.forename: Jacob
authors.initials: J
authors.lastname: Andersen
authors.forename: Mette
authors.initials: M
authors.lastname: Thomsen
authors.forename: Stinna M R
authors.initials: SM
authors.lastname: Hansen
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.forename: Albin
authors.initials: A
authors.lastname: Sandelin
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010449:Peptide Mapping / Q000379:methods; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins