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The Journal of Neuroscience, December 15, 1998, 18(24):10304-10309
Protein Kinase A Activity May Kinetically Upregulate the Striatal Transporter for Dopamine
Melissa Batchelor1 and James O. Schenk1, 2, 3 Departments of 1 Chemistry and 2 Biochemistry and Biophysics, and 3 Programs in Pharmacology/Toxicology and Neuroscience, Washington State University, Pullman, Washington 99164
The neuronal dopamine transporter (DAT) plays a key role in terminating dopaminergic chemical neurotransmission; thus, the study of the regulation of DAT activity is important in defining parameters relevant to the control of dopaminergic neurotransmission. Interpretation of the results from previous work of this laboratory suggests that occupation of presynaptic autoreceptors increases DAT activity. Second messenger signaling related to kinetic upregulation of DAT has not been examined previously. However, others have shown that protein kinase C activity may downregulate DAT activity, whereas protein kinase A has shown variable results. Herein it is shown that protein kinase A activity mediates the kinetic upregulation of DAT. Quinpirole increased DAT activity that was blocked by sulpiride and the protein kinase A selective inhibitor H-89. Brief incubations with forskolin and 8-bromo-cAMP (8-Br-cAMP) were found to stimulate striatal DAT activity by increasing the Vmax of transport without affecting the Km. Exposures >15 min had no effect. The 8-Br-cAMP-stimulated increases in DAT activity were blocked by pre-exposure to H-89. Thus, second messenger signaling via the cAMP cascade may mediate kinetic upregulation of DAT. Kinetic analyses of the results suggest that either insertion of DAT into the membrane or activation of pre-existing DAT within the membrane mediates the regulation.
Key words: dopamine transporter; protein kinase A; rotating disk electrode voltammetry; striatum; 8-Br-cAMP; forskolin; quinpirole; sulpiride; H-89; H-7; H-9
Copyright © 1998 Society for Neuroscience 0270-6474/98/182410304-06$05.00/0
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