Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D2 and D4 receptors

Cho, Dong-Im; Beom, SunRyeo; Tol, Hubert H.M. Van; Caron, Marc G.; Kim, Kyeong-Man

doi:10.1016/j.bbrc.2006.09.090

Cited by 46 publications

(37 citation statements)

References 29 publications

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“…Future studies will examine possible G protein interactions that might be involved in the mechanism of the reversal of DA inhibition in the VTA. Desensitization of D2 receptors has been observed in some expression systems (Namkung and Sibley, 2004;Cho et al, 2006). Desensitization has been well studied in other G protein-coupled receptors, such as the ␤-adrenergic receptor.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Prolonged Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area

Nimitvilai¹,

Brodie²

2010

J Pharmacol Exp Ther

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Drug abuse-induced plasticity of putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons may play an important role in changes in the mesocorticolimbic system that lead to the development of addiction. In the present study, extracellular recordings were used to examine timedependent effects of dopamine (DA) on pDAergic VTA neurons in rat brain slices. Administration of DA (2.5-10 M) for 40 min resulted in inhibition followed by partial or full reversal of that inhibition. The reduced sensitivity to DA inhibition lasted 30 to 90 min after washout of the long-term dopamine administration. The inhibition reversal was not observed with 40-min administration of the D2 agonist quinpirole (25-200 nM), so this phenomenon was not the result of desensitization induced solely by stimulation of D2 DA receptors. Inhibition reversal could be observed with the coapplication of quinpirole and the D1/D5 agonist SKF38393 [(Ϯ)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], suggesting a D1/D5 mechanism for the reversal. Furthermore, D1/D5 antagonists, given in the presence of prolonged DA exposure, prevented the inhibition reversal. Application of 3 M quinpirole caused desensitization to low quinpirole concentrations that was blocked by a D1/D5 antagonist. These data suggest that coactivation of D1/D5 receptors and D2 receptors in the VTA results in desensitization of autoinhibitory D2 receptors. Prolonged increases in pDAergic tone in the VTA that may occur in vivo with drugs of abuse could reduce the regulation of firing by D2 dopamine receptor activation, producing long-term alteration in information processing related to reward and reinforcement.

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Section: Discussionmentioning

confidence: 99%

Reversal of Prolonged Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area

Nimitvilai¹,

Brodie²

2010

J Pharmacol Exp Ther

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“…Since its dose dependence, we speculate that the reduced drug effect in the hyperactive groups of mice could be due to enhanced D2 receptor desensitization. Among DA receptors, the D2 is particularly sensitive to agonist-induced phosphorylation and b-arrestin and/or GRK2/3-mediated sequestration (Cho et al, 2006). Drug disposition differences between WT4WT and hyperactive animals are also possible but less likely because the similar response of the different groups of animals to the low dose of quinpirole.…”

Section: Wild-type Offspring Of H Mothers Have Altered D2 Receptor Fumentioning

confidence: 99%

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

Zupan

Tóth

2008

Neuropsychopharmacol

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Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Males are more severely affected than heterozygote (H) females, who, as carriers, have a 50% chance of transmitting the mutated allele in each pregnancy. fmr-1 knockout (KO) mice reproduce fragile X symptoms, including hyperactivity, seizures, and abnormal sensory processing. In contrast to the expectation that wild-type (WT) males born to H (fmr-1 + /À ) mothers (H4WT) are behaviorally normal and indistinguishable from WT males born to WT mothers (WT4WT); here, we show that H4WT offspring are more active than WT4WT offspring and that their hyperactivity is similar to male KO mice born to H or KO (fmr-1 À/À ) mothers (H4KO/KO4KO). H4WT mice, however, do not exhibit seizures or abnormal sensory processing. Consistent with their hyperactivity, the effect of the D2 agonist quinpirole is reduced in H4WT as well as in H4KO and KO4KO mice compared to WT4WT offspring, suggesting a diminished feedback inhibition of dopamine release. Our data indicate that some aspects of hyperactivity and associated dopaminergic changes in 'fragile X' mice are a maternal fmr-1 genotype rather than an offspring fmr-1 genotype effect.

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“…Receptor endocytosis can be broadly categorized into clathrin-mediated and clathrin-independent processes. Clathrin-mediated endocytosis (CME) is characterized by the formation of a partially invaginated membrane structure with a clathrin-coated cytoplasmic surface, followed by the pinching off of the invaginated clathrin-coated vesicles with the help of dynamin [3][4][5]. This pathway requires the coordinated interplay of a number of adaptor and accessory molecules, including the adaptor protein (AP) 2 complex, amphiphysin, and dynamin, as well as G proteincoupled receptor kinases (GRK)/β-arrestins that phosphorylate and connect receptors to clathrin and the AP2 complex [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Selectivity of commonly used inhibitors of clathrin-mediated and caveolae-dependent endocytosis of G protein–coupled receptors

Guo

Zhang

Zheng

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Among the multiple G protein-coupled receptor (GPCR) endocytic pathways, clathrin-mediated endocytosis (CME) and caveolar endocytosis are more extensively characterized than other endocytic pathways. A number of endocytic inhibitors have been used to block CME; however, systemic studies to determine the selectivity of these inhibitors are needed. Clathrin heavy chain or caveolin1-knockdown cells have been employed to determine the specificity of various chemical and molecular biological tools for CME and caveolar endocytosis. Sucrose, concanavalin A, and dominant negative mutants of dynamin blocked other endocytic pathways, in addition to CME. In particular, concanavalin A nonspecifically interfered with the signaling of several GPCRs tested in the study. Decreased pH, monodansylcadaverine, and dominant negative mutants of epsin were more specific for CME than other treatments were. A recently introduced CME inhibitor, Pitstop2™, showed only marginal selectivity for CME and interfered with receptor expression on the cell surface. Blockade of receptor endocytosis by epsin mutants and knockdown of the clathrin heavy chain enhanced the β2AR-mediated ERK activation. Overall, our studies show that previous experimental results should be interpreted with discretion if they included the use of endocytic inhibitors that were previously thought to be CME-selective. In addition, our study shows that endocytosis of β2 adrenoceptor through clathrin-mediated pathway has negative effects on ERK activation.

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Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D2 and D4 receptors

Cited by 46 publications

References 29 publications

Reversal of Prolonged Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area

Reversal of Prolonged Dopamine Inhibition of Dopaminergic Neurons of the Ventral Tegmental Area

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

Selectivity of commonly used inhibitors of clathrin-mediated and caveolae-dependent endocytosis of G protein–coupled receptors

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