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Distinct recognition of substrates by the human and Drosophila serotonin transporters


Distinct recognition of substrates by the human and Drosophila serotonin transporters



Journal of Pharmacology and Experimental Therapeutics 306(1): 338-346



ISSN/ISBN: 0022-3565

PMID: 12682215

DOI: 10.1124/jpet.103.048751

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.

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Accession: 003715959

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