Modulation of the neuronal dopamine transporter activity by the metabotropic glutamate receptor mGluR5 in rat striatal synaptosomes through phosphorylation mediated processes

There is considerable evidence that the activity of the neuronal dopamine t ransporter (DAT) is dynamically regulated and a putative implication of its phosphorylation in this process has been proposed. However, there is littl e information available regarding the nature of physiological stimuli that contribute to the endogenous control of the DAT function. Based on the clos e relationship between glutamatergic and dopaminergic systems in the striat um, we investigated the modulation of the DAT activity by metabotropic glut amate receptors (mGluRs). Short-term incubations of rat striatal synaptosom es with micromolar concentrations of the group I mGluR selective agonist (S )-3,5-dihydroxyphenylglycine were found to significantly decrease the DAT c apacity and efficiency. This alteration was completely prevented by a highl y selective mGluRS antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochlo ride (MPEP). The effect of (S)-3,5-dihydroxyphenylglycine was also inhibite d by staurosporine and by selective inhibitors of protein kinase C and calc ium calmodulin-dependent protein kinase II. Co-application of okadaic acid prolonged the transient effect of the agonist, supporting a critical role f or phosphorylation in the modulation of the DAT activity by mGluRs. In conc lusion, we propose that striatal mGluR5 contribute to the control of the DA T activity through concomitant activation of both protein kinase C and calc ium calmodulin-dependent protein kinase II.