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Molecular Pharmacology

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Research ArticleArticle

Interactions of Tryptamine Derivatives with Serotonin Transporter Species Variants Implicate Transmembrane Domain I in Substrate Recognition

Erika M. Adkins, Eric L. Barker and Randy D. Blakely
Molecular Pharmacology March 2001, 59 (3) 514-523; DOI: https://doi.org/10.1124/mol.59.3.514
Erika M. Adkins
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Eric L. Barker
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Randy D. Blakely
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Abstract

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is responsible for the inactivation of synaptic 5-HT and is also a target for multiple psychostimulants. Despite the critical role of SERT in 5-HT inactivation and psychostimulant response, many aspects of the transporter's recognition of ligands are poorly defined. We took advantage of sequence divergence of SERT species variants to identify structural determinants of substrate recognition. Tryptamine derivatives with substitutions at the 4 and 7 positions on the phenyl ring, the indole nitrogen, and the β position show up to 40-fold potency differences for inhibiting [3H]5-HT transport in cells transfected with either human or Drosophila melanogaster SERT cDNAs. Species selectivities of these derivatives were largely recapitulated in antagonist binding. Human/D. melanogaster SERT chimera studies implicated the first two SERT transmembrane domains (TMDs) in the potency of the indole nitrogen-substituted compoundsN-isopropyltryptamine (NIT), 5-methoxy-N-isopropyltryptamine (5-MNIT), and the 7-substituted compound 7-benzyloxytryptamine (7BT). Potency differences of analogs with substitutions at the 4 and β positions are influenced by sequences distal to this region. Within TMD I-II, species-scanning mutagenesis implicated a single residue (Y95 in human SERT, F90 in D. melanogaster SERT) in the recognition of NIT, 5-MNIT, and 7BT. Remarkably, this is the same site we established previously in species-specific recognition of the antagonists citalopram and mazindol. These findings support a critical role for TMD I residues in defining shared aspects of SERT substrate and antagonist recognition.

Footnotes

    • Received September 7, 2000.
    • Accepted November 17, 2000.
  • Send reprint requests to: Randy D. Blakely, Ph.D., Rm 419, MRBII, Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37232-6420. E-mail:randy.blakely{at}mcmail.vanderbilt.edu

  • This work was supported in part by National Institutes of Health Grants MH12399 (E.M.A.) and DA07390 (R.D.B.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (3)
Molecular Pharmacology
Vol. 59, Issue 3
1 Mar 2001
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Research ArticleArticle

Interactions of Tryptamine Derivatives with Serotonin Transporter Species Variants Implicate Transmembrane Domain I in Substrate Recognition

Erika M. Adkins, Eric L. Barker and Randy D. Blakely
Molecular Pharmacology March 1, 2001, 59 (3) 514-523; DOI: https://doi.org/10.1124/mol.59.3.514

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Research ArticleArticle

Interactions of Tryptamine Derivatives with Serotonin Transporter Species Variants Implicate Transmembrane Domain I in Substrate Recognition

Erika M. Adkins, Eric L. Barker and Randy D. Blakely
Molecular Pharmacology March 1, 2001, 59 (3) 514-523; DOI: https://doi.org/10.1124/mol.59.3.514
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