chi -conopeptide MrIA partially overlaps the desipramine and cocaine binding sites on the human norepinephrine transporter

doi:10.1074/jbc.M213101200

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Papers In Press, published online ahead of print July 1, 2003
J. Biol. Chem, 10.1074/jbc.M213101200
Submitted on December 23, 2002
Revised on July 1, 2003
Accepted on July 1, 2003

$chi$ -conopeptide MrIA partially overlaps the desipramine and cocaine binding sites on the human norepinephrine transporter

Lesley J. Bryan-Lluka, Heinz Bönisch, and Richard J. Lewis

Institute for Molecular Bioscience, Brisbane, Queensland 4072

Corresponding Author: r.lewis{at}imb.uq.edu.au

The interactions of $chi$ -conopeptide MrIA with the human norepinephrine transporter (hNET) were investigated by determining the effects of hNET point mutations on the inhibitory potency of MrIA. The mutants were produced by site-directed mutagenesis and expressed in COS-7 cells. The potency of MrIA was greater for inhibition of uptake by hNET of [³H]norepinephrine (K_i 1.89 $mu$ M) than [³H]dopamine (K_i 4.33 $mu$ M), and the human dopamine transporter (hDAT) and serotonin transporter were not inhibited by MrIA (to 7 $mu$ M). Of 18 mutations where hNET amino acid residues were exchanged to those of hDAT, MrIA had increased potency for inhibition of [³H]norepinephrine uptake for three mutations (in predicted extracellular loops 3 and 4 and transmembrane domain (TMD) 8), and decreased potency for one mutation (in TMD6 and intracellular loop (IL) 3). Of 12 additional mutations in TMDs 2, 4, 5 and 11 and IL1, three mutations (in TMD2 and IL1) had reduced MrIA inhibitory potency. All other mutations tested had no influence on MrIA potency. Comparison of the results with previous data for desipramine and cocaine inhibition of norepinephrine uptake by these mutant hNETs reveals that MrIA binding to hNET occurs at a site that is distinct from, but overlaps with, binding sites for tricyclic antidepressants and cocaine.

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