Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor

Lee, Frank J.S.; Lin, Pei; Moszczynska, Anna; Vukusic, Brian; Fletcher, Paul; Liu, Fang

doi:10.1038/sj.emboj.7601656

Cited by 185 publications

(230 citation statements)

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“…D2 autoreceptors have been found to associate with DAT, and support DAT trafficking (Bolan et al, 2007;Lee et al, 2007). Thus, our results are consistent with recent SPECT data showing reduced striatal DAT binding in PD patients with ICDs .…”

Section: Discussion [11c] Flb-457 Bp In the Midbrainsupporting

confidence: 82%

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Ray

Miyasaki

Zurowski

et al. 2012

Neurobiology of Disease

121

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Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

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Section: Discussion [11c] Flb-457 Bp In the Midbrainsupporting

confidence: 82%

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Ray

Miyasaki

Zurowski

et al. 2012

Neurobiology of Disease

121

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“…Several DAT-interacting proteins have been identified (for a recent review, see ref. 9), and, whereas the physical and functional coupling between DAT and various G protein-coupled receptors have been hypothesized, experimental data were reported only for the trace amine receptors and the dopamine D2 receptor (11)(12)(13). We show here that a putative peptidergic G protein-coupled receptor, GPR37, plays an important role in the regulation of DAT activity.…”

Section: Discussionmentioning

confidence: 85%

“…The increase or decrease of DAT expression in the presynaptic membranes results in decreased or increased synaptic DA concentration, respectively, thus regulating multiple post-and presynaptic signaling pathways mediated by D1-like and D2-like dopamine receptors (10). Although several groups have proposed the physical and functional coupling between DAT and various G protein-coupled receptors, experimental data were reported only for trace amine and DA D2 receptors (11)(12)(13). Furthermore, proteins directly involved in PD, such as parkin and ␣-synuclein, interact with DAT (14)(15)(16).…”

mentioning

confidence: 98%

GPR37 associates with the dopamine transporter to modulate dopamine uptake and behavioral responses to dopaminergic drugs

Marazziti

Mandillo

Pietro

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

100

106

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The orphan G protein-coupled receptor 37 (GPR37) is a substrate of parkin; its insoluble aggregates accumulate in brain samples of Parkinson's disease patients. We report here that GPR37 interacts with the dopamine transporter (DAT) and modulates DAT activity. GPR37 and DAT were found colocalized in mouse striatal presynaptic membranes and in transfected cells and their interaction was confirmed by coimmunoprecipitation assays. Gpr37-null mutant mice showed enhanced DAT-mediated dopamine uptake in striatal membrane samples, with a significant increase in the number of plasma membrane DAT molecules. The null mutant mice also exhibited a decrease in cocaine-induced locomotor activity and in catalepsy induced by dopamine receptor antagonists. These results reveal the specific role of GPR37, a putative peptidergic G proteincoupled receptor, in modulating the functional expression of DAT and the behavioral responses to dopaminergic drugs.G protein-coupled receptor ͉ Parkinson's disease ͉ dopamine transporter T he orphan G protein-coupled receptor 37 (GPR37) is homologous to endothelin (ET B -R) and bombesin (GRP-R, NMB-R) receptors (1) and it is highly expressed in mammalian brain oligodendrocytes, Purkinje cells, and neurons belonging to the CA3 hippocampal region and to the substantia nigra (SN) pars compacta (2). GPR37 is a substrate of the ubiquitin-protein ligase parkin, and it has been named parkin-associated endothelin-like receptor (PAEL-R) (3). An insoluble form of GPR37 is accumulated in brain samples of Parkinson's disease (PD) patients, and the overexpression of GPR37 in cell cultures, in the absence of parkin, can lead to unfolded protein-induced cell death (3, 4). Little is known about the physiological function of the receptor in the brain and in dopaminergic neurons in particular, although it has been speculated that the aggregation of GPR37 in insoluble complexes is responsible for the preferential loss of SN neurons through the endoplasmic reticulum-specific apoptotic pathway (5, 6). Recent data reported an interaction between GPR37, the head activator neuropeptide and its binding protein (sorting protein-related receptor; SorLA), supporting the hypothesis that GPR37 is involved in neuronal cell survival (7). To investigate the receptor's function, we generated homozygous Gpr37-null mutant mice, which exhibit a reduction in striatal dopamine (DA) content, specific locomotor deficits, and enhanced sensitivity to amphetamine (8).Several binding partners for the DA transporter (DAT) have been identified, suggesting that a regulated multiprotein complex controls its synthesis, targeting, and expression at specific cellular membrane domains (9). Presynaptic DAT expression is of crucial importance in modulating the synaptic availability of DA at nigrostriatal synapses, and its regulation is dynamically controlled for the maintenance of normal dopaminergic neurotransmission. The increase or decrease of DAT expression in the presynaptic membranes results in decreased or increased synaptic DA concentration, ...

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“…Mice lacking the DA D2R exhibit attenuated cocaine-induced PPI deficits, while mice administered the D2/D3R antagonist raclopride fail to show a cocaine-induced disruption in PPI. The D2R has a direct protein-to-protein link to the presynaptic DA transporter (Lee et al, 2007), known to regulate dopaminergic tone, which could explain the attenuated cocaineinduced PPI deficits in D2R KO mice. These observations are consistent with the proposal by Xu (1998) that D3Rs modulate the response to psychostimulants by inhibiting the cooperative effects of postsynaptic D 1 -and D 2 -family receptors (Daly and Waddington, 1992) at a systems level.…”

Section: Discussionmentioning

confidence: 99%

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

Doherty

Masten

Powell

et al. 2007

Neuropsychopharmacol

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Deficits in prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, are characteristics of schizophrenia and related neuropsychiatric disorders. Previous studies in mice demonstrate a contribution of dopamine (DA) D 1 -family receptors in modulating PPI and DA D 2 receptors (D2R) in mediating the PPI-disruptive effects of amphetamine. To examine further the contributions of DA receptor subtypes in PPI, we used a combined pharmacological and genetic approach. In congenic C57BL/6 J wildtype mice, we tested whether the D1R antagonist SCH23390 or the D2/3R antagonist raclopride would attenuate the effects of the indirect DA agonist cocaine (40 mg/kg). Both the D1R and D2/3R antagonists attenuated the cocaine-induced PPI deficit. We also tested the effect of cocaine on PPI in wild-type and DA D1R, D2R, or D3R knockout mice. The cocaine-induced PPI deficit was influenced differently by the three DA receptor subtypes, being absent in D1R knockout mice, partially attenuated in D2R knockout mice, and exaggerated in D3R knockout mice. Thus, the D1R is necessary for the PPI-disruptive effects of cocaine, while the D2R partially contributes to these effects. Conversely, the D3R appears to inhibit the PPI-disruptive effects of cocaine. Uncovering neural mechanisms involved in PPI will further our understanding of substrates of sensorimotor gating and could lead to better therapeutics to treat complex cognitive disorders such as schizophrenia.

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Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor

Cited by 185 publications

References 50 publications

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

GPR37 associates with the dopamine transporter to modulate dopamine uptake and behavioral responses to dopaminergic drugs

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

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