Invited Symposium: Molecular and Cellular Analysis of Dopamine and Serotonin Transporters
Liu, F. (Centre of Addiction and Mental Health, Inst. of Medical Science, University of Toronto, Canada)
McConkey, F. (Centre of Addiction and Mental Health, University of Toronto, Canada)
Pristupa, Z.B. (Centre of Addiction and Mental Health, Dept. of Psychiatry, University of Toronto, Canada)
Niznik, H.B. (Centre of Addiction and Mental Health, Departments.of Pharmacology and Psychiatry, University of Toronto, Canada)
The primary mechanism for the inactivation/recycling of DA released into the synaptic cleft from dopaminergic neurons is mediated through Na+/Cl- -dependent reuptake of DA into the presynaptic neuron via the dopamine transporter (DAT). The ability of the DAT to control DA synaptic levels implicates the importance of regulating the DAT itself. Second messengers and their effectors may be potential mechanisms through which the DAT is regulated. Previous studies have shown arachidonic acid, Ca2+ levels, calmodulin-dependent kinases, PKA- and PKC-dependent pathways to regulate DAT function. A potentially very important method of regulating the DAT may be through the activation of presynaptic D2 receptors. Studies with striatal tissue have already implicated the activation of D2 receptors in regulating DA reuptake. In our studies, we show that coexpression of recombinant D2 receptors and DAT in cells (HEK293, Ltk-) also facilitate an upregulation of DAT activity (change in Vmax from 0.4 to 1.0 pmol/105cells/min). But as opposed to previous studies, this was independent of D2 activation by agonist pretreatment which is supported by the inability of the presence of D2 antagontists to attenuate this upregulation. Interestingly, confocal immunofluorescence of cells coexpressing both DAT and D2 receptors show a robust translocation of DAT protein from the intracellular region to the cell surface, independent of D2 agonist/antagonist treatment. These studies suggest that D2 regulation of DAT may involve either direct or indirect interactions by either (i) the recruitment of mechanisms involved in the trafficking of DAT protein to the cell surface and/or (ii) through interactions with g-proteins, associated with D2 receptors.
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|Lee, F.J.S.; Liu, F.; McConkey, F.; Pristupa, Z.B.; Niznik, H.B.; (1998). Constitutive Enhancement Of hDAT Function By Dopamine D2 Receptors. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/simantov/lee0786/index.html|
|© 1998 Author(s) Hold Copyright|