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NEUROPHARMACOLOGY

Rapid Stimulation of Presynaptic Serotonin Transport by A₃ Adenosine Receptors

Departments of Pharmacology (C.-B.Z., J.A.S., W.A.H., R.D.B.) and Psychiatry (W.A.H., R.D.B.), and Center for Molecular Neuroscience (R.D.B.), Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Physiology (J.L.M., L.C.D.), University of Texas Health Science Center, San Antonio, Texas

The inactivation of synaptic serotonin (5-hydroxytryptamine, 5-HT) is largely established through the actions of the presynaptic, antidepressant-sensitive 5-HT transporter (SERT, SLC6A4). Recent studies have demonstrated post-translational regulation of SERT mediated by multiple Ser/Thr kinases, including protein kinases C and G (PKC and PKG) and p38 mitogen-activated protein kinase (MAPK), as well as the Ser/Thr phosphatase PP2A. Less well studied are specific surface receptors that target these signaling pathways to control SERT surface expression and/or catalytic rates. Using rat basophilic leukemia 2H3 cell line (RBL-2H3), we previously established that activation of A₃ adenosine receptors (A₃AR) stimulates SERT activity via both PKG and p38 MAPK (Zhu et al., 2004a). Whether A₃ARs regulate SERT in the central nervous system (CNS) is unknown. Here we report that the A₃AR agonist N⁶-(3-iodobenzyl)-N-methyl-5'carbamoyladenosine (IB-MECA) rapidly (10 min) and selectively stimulates 5-HT transport in mouse midbrain, hippocampal, and cortical synaptosomes. IB-MECA-induced stimulation of 5-HT uptake is blocked by the selective A₃AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(±)dihydropyridine-3,5-dicarboxylate (MRS1191) and is absent from synaptosomes prepared from A₃AR knockout mice. Kinetic analyses demonstrate that IB-MECA induces an increase of 5-HT transport V_max with no significant change in K_m. As in RBL-2H3 cells, IB-MECA stimulation of synaptosomal 5-HT uptake can be blocked by preincubation with PKG antagonists N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) and DT-2 (YGRKKRRQRRRPPLRK₅H), as well as by the p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Chronoamperometry studies in the anesthetized rat hippocampus support a role for A₃ARs in SERT regulation in vivo. Together, these results identify a novel, region-specific action of CNS A₃ARs in the modulation of SERT-mediated 5-HT transport that may be relevant for the etiology and/or therapy of 5-HT-linked brain disorders.

Address correspondence to: Dr. Randy D. Blakely, Suite 7140, MRBIII, Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37232-8548. E-mail: randy.blakely{at}vanderbilt.edu

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