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Papers In Press, published online ahead of print June 14, 2001
Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066
Corresponding Author: gary.rudnick{at}yale.edu
Inactivation of serotonin transporter (SERT) expressed in HeLa cells by [2-(trimethylammonium)ethyl]methanethiosulfonate (MTSET) occurred much more readily when Na+ in the reaction medium was replaced with Li+. This did not result from a protective effect of Na+, but rather a Li+-specific increase in the reactivity of Cys-109 in the first external loop (EL1) of the transporter. Li+ alone of the alkali cations caused this increase in reactivity. Replacing Na+ with N-methyl-D-glucamine (NMDG+) did not reduce the affinity of cocaine for SERT, as measured by displacement of a high affinity cocaine analog, but replacement of Na+ with Li+ led to a 2-fold increase in the KD for cocaine. Addition of either cocaine or serotonin (5-HT) protected SERT against MTSET inactivation. When SERT was expressed in Xenopus oocytes, an inward current was elicited by superfusing the cell with 5-HT (in the presence of Na+) or by replacing Na+ with Li+, but not NMDG+. MTSET treatment of oocytes in Li+, but not in Na+, decreased both 5-HT and Li+ induced currents, although 5-HT induced currents were inhibited to a greater extent. Na+ antagonized the effects of Li+ on both inactivation and current. These results are consistent with Li+ inducing a conformational change that exposes Cys-109, decreases cocaine affinity, and increases the uncoupled inward current.
J. Biol. Chem, 10.1074/jbc.M104653200
Submitted on May 22, 2001
Revised on June 13, 2001
Accepted on June 14, 2001
A lithium-induced conformational change in serotonin transporter alters cocaine binding, Ion-conductance, and reactivity of Cys-109
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