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J. Biol. Chem., Vol. 282, Issue 24, 17837-17844, June 15, 2007

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-Conotoxin and Tricyclic Antidepressant Interactions at the Norepinephrine Transporter Define a New Transporter Model^*

From the Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia

Monoamine neurotransmitter transporters for norepinephrine (NE), dopamine and serotonin are important targets for antidepressants and analgesics. The conopeptide -MrIA is a noncompetitive and highly selective inhibitor of the NE transporter (NET) and is being developed as a novel intrathecal analgesic. We used site-directed mutagenesis to generate a suite of mutated transporters to identify two amino acids (Leu⁴⁶⁹ and Glu³⁸²) that affected the affinity of -MrIA to inhibit [³H]NE uptake through human NET. Residues that increased the K_d of a tricyclic antidepressant (nisoxetine) were also identified (Phe²⁰⁷, Ser²²⁵, His²⁹⁶, Thr³⁸¹, and Asp⁴⁷³). Phe²⁰⁷, Ser²²⁵, His²⁹⁶, and Thr³⁸¹ also affected the rate of NE transport without affecting NE K_m. In a new model of NET constructed from the bLeuT crystal structure, -MrIA-interacting residues were located at the mouth of the transporter near residues affecting the binding of small molecule inhibitors.

Received for publication, November 22, 2006 , and in revised form, March 26, 2007.

^* This work was supported by National Health and Medical Research Council Program and Project Grants. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a University of Queensland Postgraduate Scholarship.

² To whom correspondence should be addressed: Institute for Molecular Bioscience (QBP), The University of Queensland, St. Lucia, 4072, Qld, Australia. Tel.: 617-3346-2984; Fax: 617-3346-2101; E-mail: r.lewis{at}imb.uq.edu.au.

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