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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut (F.K., G.R.); and Laboratory of Clinical Science, National Institutes of Mental Health, National Institutes of Health, Bethesda, Maryland (D.L.M.)
A rarely occurring variant of human serotonin transporter (hSERT) was
tested for its functional consequences in HeLa and COS-7 cells. The variant,
in which Ile-425 is converted to Val, was significantly different from wild
type with respect to its catalytic properties. In both cell types, rates of
serotonin (5-HT) transport were higher for the I425V variant. Both an increase
in Vmax and a decrease in KM caused
this increase in rate. The increase in Vmax was not
accounted for by increases in transporter expression or in the distribution of
transporter between the cell surface and intracellular pools. The decrease in
KM was accompanied by a decrease in the
KD for binding of the cocaine analog
2
-carbomethoxy-3-(4-[125I]iodophenyl)tropane. In both
HeLa and COS-7 cells, the nitric oxide donor
S-nitroso-N-acetylpenicillamine increased the activity of
wild-type hSERT to that of the variant but did not change the activity of the
I425V variant. This stimulation was prevented by the presence of
oxyhemoglobin, which quenches nitric oxide, and by an inhibitor of guanylyl
cyclase.
Address correspondence to: Gary Rudnick, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208066, New Haven, CT 06520-8066. Email: gary.rudnick{at}yale.edu
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