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The Journal of Neuroscience, October 3, 2007, 27(40):10878-10886; doi:10.1523/JNEUROSCI.0034-07.2007

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Cellular/Molecular
Serotonin Transporter Phosphorylation by cGMP-Dependent Protein Kinase Is Altered by a Mutation Associated with Obsessive–Compulsive Disorder

Yuan-Wei Zhang,¹ Joan Gesmonde,¹ Sammanda Ramamoorthy,² and Gary Rudnick¹

¹Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, and ²Department of Neurosciences, Division of Neuroscience Research, Medical University of South Carolina, Charleston, South Carolina 29425

Correspondence should be addressed to Dr. 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

Human serotonin transporter (hSERT) activity expressed in HeLa cells was stimulated by agents that release nitric oxide, stimulate soluble guanylyl cyclase, or activate cGMP-dependent protein kinase (PKG). This stimulation was blocked by a PKG inhibitor. A naturally occurring mutation, I425V, associated with obsessive–compulsive disorder and other neuropsychiatric disorders, activated hSERT and eliminated stimulation via the PKG pathway. Inhibitors of soluble guanylyl cyclase or PKG decreased activity of the I425V mutant, but not wild type, indicating that both wild-type and mutant transporters could exist in both high and low activity forms. Mutation of Thr-276 in the fifth transmembrane domain (TM5) to alanine or aspartate prevented activation of wild-type hSERT through the PKG pathway and also blocked the inhibition of I425V activity by inhibitors of the pathway. The accessibility of positions in TM5 near Thr-276 was modified in T276D, but not in I425V. These results are consistent with the hypothesis that PKG phosphorylates hSERT at Thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by TM5. The effect of the I425V mutation may shift the balance of hSERT toward the phosphorylated form, possibly by interfering with the action of a phosphatase. However, association of hSERT with protein phosphatase 2A was not decreased in the I425V mutant.

Key words: serotonin; transporter; obsessive–compulsive disorder; phosphorylation; cGMP; mutation

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Received Feb. 3, 2005; revised Aug. 22, 2007; accepted Aug. 24, 2007.

Correspondence should be addressed to Dr. 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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