TY - JOUR T1 - Distinct Recognition of Substrates by the Human and <em>Drosophila</em> Serotonin Transporters JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 338 LP - 346 DO - 10.1124/jpet.103.048751 VL - 306 IS - 1 AU - G. J. Rodríguez AU - D. L. Roman AU - K. J. White AU - D. E. Nichols AU - E. L. Barker Y1 - 2003/07/01 UR - http://jpet.aspetjournals.org/content/306/1/338.abstract N2 - 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 μM, 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. The American Society for Pharmacology and Experimental Therapeutics ER -