Interaction of Antidepressants with the Serotonin and Norepinephrine Transporters
| Autor: | Kristian Strømgaard, Stinna M. R. Hansen, Xiaobei Zhao, Lena Sørensen, Mette Thomsen, Jacob Andersen, Anders S. Kristensen, Albin Sandelin |
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| Rok vydání: | 2012 |
| Předmět: |
Neurotransmitter transporter
0303 health sciences biology Cell Biology Pharmacology Biochemistry 3. Good health Reuptake 03 medical and health sciences 0302 clinical medicine Norepinephrine transporter Serotonin Plasma Membrane Transport Proteins biology.protein Antidepressant Norepinephrine Plasma Membrane Transport Proteins Neurotransmitter transport Molecular Biology 030217 neurology & neurosurgery Serotonin transporter 030304 developmental biology |
| Zdroj: | Journal of Biological Chemistry. 287:43694-43707 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.342212 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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