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Volume 17, Number 1, Issue of January 1, 1997 pp. 45-57
Copyright ©1997 Society for NeuroscienceProtein Kinase C Activation Regulates Human Serotonin Transporters in HEK-293 Cells via Altered Cell Surface Expression
Received Aug. 21, 1996; revised Oct. 1, 1996; accepted Oct. 7, 1996.
Yan Qian1, 2, Aurelio Galli1, Sammanda Ramamoorthy1, Stefania Risso3, Louis J. DeFelice1, and Randy D. Blakely1 1 Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt School of Medicine, Nashville, Tennessee 37232-6600, 2 Graduate Program in Neuroscience, Emory University, Atlanta, Georgia 30322, and 3 Department of Pharmacology, Emory University, Atlanta, Georgia 30322
Antidepressant- and cocaine-sensitive serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) dictate clearance of extracellular 5-HT after release. To explore protein kinase C-mediated SERT regulation, we generated a stable human SERT (hSERT)-expressing cell line (293-hSERT) and evaluated modulation of 5-HT activity via studies of 5-HT flux, hSERT-mediated currents under voltage clamp, and surface distribution of SERT protein. 293-hSERT cells exhibit saturable, high-affinity, and antidepressant-sensitive 5-HT uptake as well as hSERT-dependent whole-cell currents. In these cells, the protein kinase C activator
-PMA caused a time-dependent reduction in 5-HT uptake capacity (Vmax) after acute application and a reduction in SERT-mediated currents. Effects of
-isomers, and could be blocked by treatment of cells with the protein kinase C inhibitor staurosporine. Biotinylation/immunoblot analyses showed that activity reductions are paralleled by a staurosporine-sensitive loss of surface SERT protein. These data indicate that altered surface abundance, rather than reduced catalytic transport efficiency, mediates acute PKC-dependent modulation of 5-HT uptake.
Key words: serotonin; serotonin transporter; antidepressant; protein kinase C; regulation; phosphorylation; protein trafficking
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