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Identification of residues in the serotonin transporter engaged in high affinity recognition of antidepressants and cocaine
Author(s) -
Field Julie R.,
Henry L. Keith,
Dawson Eric S.,
Blakely Randy D.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a683
Subject(s) - citalopram , serotonin transporter , pharmacology , transporter , chemistry , potency , serotonin , reuptake inhibitor , antidepressant , tricyclic , biochemistry , biology , receptor , endocrinology , gene , hippocampus , in vitro
The serotonin (5HT) transporter (SERT) is an important target for antidepressants and psychostimulants, including cocaine and ecstasy. Using an evolutionary comparison of human and Drosophila SERTs, we have identified residues in transmembrane segments (TM) 1 and 3 that influence 5HT and competitor interactions. In TM 3, replacement of isoleucine at hSERT position 172 with methionine, the residue native to dSERT, discriminates between 5HT and antagonists, demonstrating no effect on substrate potency while causing a thousand‐fold loss of potency for citalopram, as well as significant losses in potency for several selective serotonin reuptake inhibitors, tricyclic antidepressants, and cocaine. Importantly, the reciprocal mutation in dSERT, M167I, shows a significant gain of potency for citalopram, fluoxetine and cocaine, but no change in 5HT uptake properties. hSERT I172 may coordinate citalopram binding with a previously identified TM 1 residue Y95, as hSERT Y95F/I172M shows a synergistic loss in citalopram potency. The proximity of these residues is supported by the recent crystal structure of an hSERT bacterial ortholog, the leucine transporter LeuT Aa . Our data support a potential for these residues to coordinate antidepressant and substrate binding and offer new insights into mechanisms of ligand selectivity among biogenic amine neurotransmitter transporters. J.R.F. is funded by NIH 5 T32 GM07628‐28 and a grant from Forest Research Institute.