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

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Sorensen L, Andersen J, Thomsen M, Hansen SM, Zhao X, Sandelin A, Stromgaard K, Kristensen AS

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

J Biol Chem. 2012 Dec 21;287(52):43694-707. doi: 10.1074/jbc.M112.342212. Epub 2012 Oct 19.

PubMed ID

23086945 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sertraline	Sodium-dependent noradrenaline transporter	Protein	Humans	Unknown	Inhibitor Downregulator	Details