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J. Biol. Chem., Vol. 280, Issue 7, 5400-5405, February 18, 2005

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Alteration of Lithium Pharmacology through Manipulation of Phosphoadenosine Phosphate Metabolism^*

Bryan D. Spiegelberg, June dela Cruz, Tzuo-Hann Law, and John D. York

From the Departments of Pharmacology & Cancer Biology and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710

Bisphosphate 3'-nucleotidase (BPNT1 in mammals and Met22/Hal2 in yeast) is one of five members of a family of signaling phosphatases united through a common tertiary structure and inhibition by subtherapeutic doses of the antibipolar drug lithium. Here we report a role for 3'-nucleotidase and its substrate, 3'-phosphoadenosine 5'-phosphate (PAP), in mediating the cellular effects of lithium. Lithium-induced inhibition of growth in yeast cells may be overcome by dose-dependent heterologous expression of human BPNT1. Disruption of the yeast 3'-nucleotidase gene or treatment of cells with lithium results in a >80-fold accumulation of PAP and leads to potent growth inhibition. These data indicate that the accumulation of a 3'-nucleotidase substrate, such as PAP, mediates the toxicity of lithium. To further probe this model we examined the growth inhibitory effects of lithium under conditions in which PAP biosynthetic machinery was concomitantly down-regulated. Disruption of met3 or met14 genes (ATP sulfurylase or phosphosulfate kinase), transcriptional down-regulation of MET3 through methionine addition, or administration of chlorate, a widely used cell-permeable sulfurylase inhibitor, function to reduce lithium-induced intracellular PAP accumulation and lithium toxicity; all of these effects were reversed by heterologous expression of human sulfurylase and kinase. Collectively, our data support a role for 3'-nucleotidase activity and PAP metabolism in aspects of lithium's mechanism of action and provide a platform for development of novel pharmacological modulators aimed at improving therapies for the treatment of bipolar disorder.

Received for publication, July 13, 2004 , and in revised form, December 3, 2004.

^* This work is supported by funds from the Howard Hughes Medical Institute and by National Institutes of Health Grant R01 HL-55672. 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.

Present address: Dept. of Pharmacology, Vanderbilt University, Nashville, TN 37232.

To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Howard Hughes Medical Institute, Duke University Medical Center, DUMC 3813, Durham, NC 27710. Tel.: 919-681-6414; Fax: 919-668-0991; E-mail: yorkj{at}duke.edu.

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