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J. Biol. Chem., Vol. 280, Issue 16, 15649-15658, April 22, 2005

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p38 MAPK Activation Elevates Serotonin Transport Activity via a Trafficking-independent, Protein Phosphatase 2A-dependent Process^*

Chong-Bin Zhu, Ana M. Carneiro¶, Wolfgang R. Dostmann||, William A. Hewlett, and Randy D. Blakely¶**

From the Departments of Psychiatry and Pharmacology, and the ^¶Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548 and the ^||Department of Pharmacology, University of Vermont, Burlington, Vermont 05405-0075

Presynaptic, plasma membrane serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) clear 5-HT following vesicular release and are regulated through trafficking-dependent pathways. Recently, we (Zhu, C.-B., Hewlett, W. A., Feoktistov, I., Biaggioni, I., and Blakely, R. D. (2004) Mol. Pharmacol. 65, 1462–1474) provided evidence for a trafficking-independent mode of SERT regulation downstream of adenosine receptor (AR) activation that is sensitive to p38 MAPK inhibitors. Here, we probe this pathway in greater detail, demonstrating elevation of 5-HT transport by multiple p38 MAPK activators (anisomycin, H₂O₂, and UV radiation), in parallel with p38 MAPK phosphorylation, as well as suppression of anisomycin stimulation by p38 MAPK siRNA treatments. Studies with transporter-transfected Chinese hamster ovary cells reveal that SERT stimulation is shared with the human norepinephrine transporter but not the human dopamine transporter. Saturation kinetic analyses of anisomycin-SERT activity reveal a selective reduction in 5-HT K_m supported by a commensurate increase in 5-HT potency (K_i) for displacing surface antagonist binding. Anisomycin treatments that stimulate SERT activity do not elevate surface SERT surface density whereas stimulation is lost with preexposure of cells to the surface-SERT inactivating reagent, 2-(trimethylammonium)ethyl methane thiosulfonate. Guanylyl cyclase (1H-(1,2,4)-oxadiazolo[4,3-a]-quinoxalin-1-one) and protein kinase G inhibitors (H8, DT-2) block AR stimulation of SERT yet fail to antagonize SERT stimulation by anisomycin. We thus place p38 MAPK activation downstream of protein kinase G in a SERT-catalytic regulatory pathway, distinct from events controlling SERT surface density. In contrast, the activity of protein phosphatase 2A inhibitors (fostriecin and calyculin A) to attenuate anisomycin stimulation of 5-HT transport suggests that protein phosphatase 2A is a critical component of the pathway responsible for p38 MAPK up-regulation of SERT catalytic activity.

Received for publication, September 21, 2004 , and in revised form, February 2, 2005.

^* This work was supported by National Institute on Drug Abuse Grants DA07390 (to R. D. B.) and T32-MH65782-02 (to A. M. C.), by National Institutes of Health Grant HL68991 and the Totman Medical Research Trust (to W. R. D.), and by the Obsessive-Compulsive Disorder/Tourette Program at Vanderbilt University. 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.

^** To whom correspondence should be addressed: Center for Molecular Neuroscience, Suite 7140 MRBIII, Vanderbilt School of Medicine, Nashville, TN 37232-8548. Tel.: 615-936-3705; Fax: 615-936-3040; E-mail: randy.blakely{at}vanderbilt.edu.

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