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

Abstract

There is considerable evidence that the activity of the neuronal dopamine transporter (DAT) is dynamically regulated and a putative implication of its phosphorylation in this process has been proposed. However, there is little information available regarding the nature of physiological stimuli that contribute to the endogenous control of the DAT function. Based on the close relationship between glutamatergic and dopaminergic systems in the striatum, we investigated the modulation of the DAT activity by metabotropic glutamate receptors (mGluRs). Short-term incubations of rat striatal synaptosomes with micromolar concentrations of the group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine were found to signi®cantly decrease the DAT capacity and ef®ciency. This alteration was completely prevented by a highly selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). The effect of (S)-3,5-dihydroxyphenylglycine was also inhibited by staurosporine and by selective inhibitors of protein kinase C and calcium calmodulin-dependent protein kinase II. Co-application of okadaic acid prolonged the transient effect of the agonist, supporting a critical role for phosphorylation in the modulation of the DAT activity by mGluRs. In conclusion, we propose that striatal mGluR5 contribute to the control of the DAT activity through concomitant activation of both protein kinase C and calcium calmodulin-dependent protein kinase II.

Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice

“…Because mGlu5 receptors are found in striatal dopaminergic terminals where they negatively modulate DAT activity (Page et al, 2001) …”

Amphetamine Regulation of Dopamine Transport

“…In 2000, Saunders and colleagues proposed a novel action of AMPH by demonstrating that acute application of AMPH reduces hDAT cell surface expression (11). Sorkina and colleagues (12) recently extended this observation by showing that AMPH induced an intracellular accumulation of hDAT in early and late endosomal vesicles, which coexpress the endosomal proteins Rab5, Rab11, Hrs, and EEA.1.Regulators of DAT activity include AMPH and cocaine (11-16), G-protein-coupled receptors such as the D 2 and mGluR5 receptors (17,18), kinases such as protein kinase C, phosphatidylinositol 3-kinase, tyrosine kinase, and Ca 2ϩ /calmodulin kinase (12, 13, 19 -23), and transporter interacting proteins (24,25). In addition, some of these studies suggest that the regulation of DAT activity may originate from a change in DAT cell surface expression (11, 13-17, 19, 21, 23-25).…”

“…Regulators of DAT activity include AMPH and cocaine (11)(12)(13)(14)(15)(16), G-protein-coupled receptors such as the D 2 and mGluR5 receptors (17,18), kinases such as protein kinase C, phosphatidylinositol 3-kinase, tyrosine kinase, and Ca 2ϩ /calmodulin kinase (12, 13, 19 -23), and transporter interacting proteins (24,25). In addition, some of these studies suggest that the regulation of DAT activity may originate from a change in DAT cell surface expression (11, 13-17, 19, 21, 23-25).…”

Stimulation of group I mGlu receptors in the ventrotegmental area enhances extracellular dopamine in the rat medial prefrontal cortex

“…The selective group I mGlu receptor agonist (R,S)3, 5-dihydroxyphenylglycine (DHPG) (Schoepp et al 1999) raised extracellular DA in the rat striatum (Bruton et al 1999), reduced the efficacy of the DA transporter (Page et al 2001), increased the firing activity of DA neurons of the substantia nigra compacta (SNc) and ventrotegmental area (VTA) (Prisco et al 2002;Zheng and Johnson 2002) and enhanced locomotor activity (Swanson and Kalivas 2000). Apart from a recent report that selective blockade of the mGlu5 receptor increased extracellular DA in the mPFC (Homayoun et al 2004), no information is available on the effect of selective agonists and antagonists of group I mGlu receptor subtypes on mPFC DA release in vivo.…”