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J Biol Chem, Vol. 273, Issue 31, 19459-19468, July 31, 1998
From the Department of Pharmacology and Center for Molecular
Neuroscience, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232-6600, the Human and Drosophila melanogaster
serotonin (5-HT) transporters (SERTs) exhibit similar 5-HT transport
kinetics and can be distinguished pharmacologically by many, but not
all, biogenic amine transporter antagonists. By using human and
Drosophila SERT chimeras, major determinants of potencies
of two transporter antagonists, mazindol and citalopram, were tracked
to the amino-terminal domains encompassing transmembrane domains I and
II. Species-scanning mutagenesis, whereby amino acid substitutions are
made switching residues from one species to another, was employed on
the eight amino acids that differ between human and
Drosophila SERTs in this region, and antagonist potencies
were reassessed in 5-HT uptake assays. A single mutation in
transmembrane domain I of human SERT, Y95F, shifted both citalopram and
mazindol to Drosophila SERT-like potencies. Strikingly,
these potency changes were in opposite directions suggesting
Tyr95 contributes both positive and negative determinants
of antagonist potency. To gain insight into how the Y95F mutant might
influence mazindol potency, we determined how structural variants of
mazindol responded to the mutation. Our studies demonstrate the
importance of the hydroxyl group on the heterocyclic nucleus of
mazindol for maintaining species-selective recognition of mazindol and suggest that transmembrane domain I participates in the formation of
antagonist-binding sites for amine transporters.
High Affinity Recognition of Serotonin Transporter Antagonists
Defined by Species-scanning Mutagenesis
AN AROMATIC RESIDUE IN TRANSMEMBRANE DOMAIN I DICTATES
SPECIES-SELECTIVE RECOGNITION OF CITALOPRAM AND MAZINDOL
, Department of
Medicinal Chemistry and Molecular Pharmacology, Purdue University
School of Pharmacy, West Lafayette, Indiana 47907, the
§ Charles A. Dana Research Institute, Drew University,
Madison, New Jersey 07940, and the ¶ Department of Psychiatry
and Laboratory of Molecular Neurobiology, Clarke Institute of
Psychiatry, Toronto, Ontario M5T 1RS, Canada
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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