Distinct recognition of substrates by the human and Drosophila serotonin transporters

G J Rodríguez; D L Roman; K J White; D E Nichols; E L Barker

doi:10.1124/jpet.103.048751

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Distinct recognition of substrates by the human and Drosophila serotonin transporters

Journal article

Peer reviewed

Distinct recognition of substrates by the human and Drosophila serotonin transporters

G J Rodríguez, D L Roman, K J White, D E Nichols and E L Barker

The Journal of pharmacology and experimental therapeutics, Vol.306(1), pp.338-346

07/2003

DOI: 10.1124/jpet.103.048751

PMID: 12682215

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Abstract

The human and Drosophila serotonin transporters (hSERT and dSERT, respectively) were used to explore differences in substrate properties. hSERT and dSERT showed similar Km values for 5-hydroxytryptamine (5-HT; serotonin) transport (1.2 and 0.9 micro M, respectively), suggesting similar recognition of 5-HT by the two species variants. Although dSERT cell surface expression was approximately 8-fold lower than that of hSERT, dSERT does appear to have a 2-fold faster turnover number for inward transport of 5-HT. Interestingly, another substrate, N-methyl-4-phenylpyridinium (MPP+), was transported only by hSERT. However, MPP+ inhibited 5-HT uptake in both species variants with similar potencies. Two cross-species chimeras, H1-118D119-627 and H1-281D282-476H477-638, were also unable to transport MPP+, implicating the role of transmembrane domains V to IX in the substrate permeation pathway. Based on exchange experiments, certain substituted-amphetamines also appear to be poor substrates at dSERT. Two-electrode voltage-clamp studies in oocytes confirmed that the amphetamines do not possess substrate-like properties for dSERT. Our data suggest distinct molecular recognition among SERT substrate classes that influence translocation mechanisms.

Cell Line

Drosophila Proteins

Membrane Glycoproteins - metabolism

Species Specificity

1-Methyl-4-phenylpyridinium - pharmacokinetics

Humans

Nerve Tissue Proteins

Serotonin Plasma Membrane Transport Proteins

Recombinant Fusion Proteins - metabolism

Animals

Carrier Proteins - metabolism

Biological Transport

Dopamine Agents - pharmacokinetics

Membrane Transport Proteins

Serotonin - metabolism

Drosophila - metabolism

Amphetamine - pharmacokinetics

Details

Title: Subtitle: Distinct recognition of substrates by the human and Drosophila serotonin transporters
Creators: G J Rodríguez - Department of Medical Chemistry and Molecular Phamacology, Pudue University School of Pharmacy, I575 Stadium Mall Dr., West Lafayette IN, 47907-2091, USA
D L Roman
K J White
D E Nichols
E L Barker
Resource Type: Journal article
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.306(1), pp.338-346
Publisher: United States
DOI: 10.1124/jpet.103.048751
PMID: 12682215
ISSN: 0022-3565
eISSN: 1521-0103
Grant note: MH60221 / NIMH NIH HHS
Language: English
Date published: 07/2003
Academic Unit: Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984065485002771

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