Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Fiorentini, Chiara; Gardoni, Fabrizio; Spano, PierFranco; Luca, Monica Di; Missale, Cristina

doi:10.1074/jbc.m213140200

Cited by 207 publications

(197 citation statements)

References 41 publications

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“…First, western blot studies consistently detecte a substantial amount of D1 and D2 receptors in purified PSD fractions [41][42][43]. Second, DA receptors interact and co-localize with a number of PSD proteins in dendritic spines (see Section 6 below).…”

Section: Subcellular Localization Of Da Receptorsmentioning

confidence: 97%

“…Besides short peptide sequences involved in G protein and arrestin binding, the remaining portions of these intracellular domains are presumably free to interact with other proteins. Using approaches such as co-immunoprecipitation and the yeast two-hybrid system, an increasing number of DRIPs are being identified [41][42][43]53,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]. The confirmed DRIPs and their suggested functions are summarized in Table 1.…”

Section: Da Receptor-interacting Proteins (Drips)mentioning

confidence: 99%

“…When D1 and NR1 were coexpressed in individual cells in the absence of the NR2B subunit, both were retained in cytoplasmic compartments. However, in the presence of NR2B, the NR1-D1 receptor complex was translocated to the plasma membrane, suggesting that D1 and NMDARs were assembled within intracellular compartments as constitutive heteromeric complexes [41]. In both heterologous cells and cultured neurons, activation of NMDARs recruited D1 receptors to the plasma membrane via a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent mechanism, resulting in enhancement of D1-mediated cAMP accumulation [84].…”

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confidence: 99%

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Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

110

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Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

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Section: Subcellular Localization Of Da Receptorsmentioning

confidence: 97%

Section: Da Receptor-interacting Proteins (Drips)mentioning

confidence: 99%

mentioning

confidence: 99%

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Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

110

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“…Important clues are provided by our study in the basolateral amygdala, where we show that application of dopamine significantly decreases glutamate NMDA receptor-mediated postsynaptic currents through postsynaptic mechanisms, which may include co-trafficking of D1R and NMDA receptor . This is suggested by known protein-protein interactions between the C-terminals of D1R and the NR1 subunit of NMDA receptor (Lee et al, 2002;Fiorentini et al, 2003;Pei et al, 2004;Pickel et al, 2006). Dopaminergic and glutamatergic terminals converge on the same dendritic spine in the Acb (Sesack and Pickel, 1990;Pinto et al, 2003), where NMDA receptor antagonists also disrupt sensorimotor gating (Mansbach and Geyer, 1989;Bakshi et al, 1999).…”

Section: Apomorphine-and As-induced Changes In D1r Distribution In Thmentioning

confidence: 99%

Dendritic distributions of dopamine D1 receptors in the rat nucleus accumbens are synergistically affected by startle-evoking auditory stimulation and apomorphine

Hara

Pickel

2007

Neuroscience

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Prepulse inhibition of the startle response to auditory stimulation (AS) is a measure of sensorimotor gating that is disrupted by the dopamine D1/D2 receptor agonist, apomorphine. The apomorphine effect on prepulse inhibition is ascribed in part to altered synaptic transmission in the limbicassociated shell and motor-associated core subregions of the nucleus accumbens (Acb). We used electron microscopic immunolabeling of dopamine D1 receptors (D1Rs) in the Acb shell and core to test the hypothesis that region-specific redistribution of D1Rs is a short-term consequence of AS and/or apomorphine administration. Thus, comparisons were made in the Acb of rats sacrificed one hour after receiving a single subcutaneous injection of vehicle (VEH) or apomorphine (APO) alone or in combination with startle-evoking AS (VEH+AS, APO+AS). In both regions of all animals, the D1R immunoreactivity was present in somata and large, as well as small, presumably more distal dendrites and dendritic spines. In the Acb shell, compared with the VEH+AS group, the APO+AS group had more spines containing D1R immunogold particles, and these particles were more prevalent on the plasma membranes. This suggests movement of D1Rs from distal dendrites to the plasma membrane of dendritic spines. Small-and medium-sized dendrites also showed a higher plasmalemmal density of D1R in the Acb shell of the APO+AS group compared with the APO group. In the Acb core, the APO+AS group had a higher plasmalemmal density of D1R in medium-sized dendrites compared with the APO or VEH+AS group. Also in the Acb core, D1R-labeled dendrites were significantly smaller in the VEH+AS group compared to all other groups. These results suggest that alerting stimuli and apomorphine synergistically affect distributions of D1R in Acb shell and core. Thus adaptations in D1R distribution may contribute to sensorimotor gating deficits that can be induced acutely by apomorphine or develop over time in schizophrenia.

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“…Similarly, in striatal postsynaptic density (PSD) preparations the C-terminal tail of the D1R, but not the D5R, coimmunoprecipitated with the NR1 subunit of the NMDA receptor (Fiorentini et al, 2003). The formation of the D1-NR1 heteromer was shown to occur through a strong and stable arginine-phosphate electrostatic interaction Woods and Ferré, 2005) and reported to be enhanced by ligand occupancy of the NMDA/glutamatebinding site of the NMDA receptor, to slow down lateral diffusion, and stabilize D1R localization in the synapse (Scott et al, 2006).…”

Section: Dopamine-nmda Receptor Heteromers: D1-nr1 D2-nr2bmentioning

confidence: 99%

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Perreault

Hasbi

O’Dowd

et al. 2013

Neuropsychopharmacol

143

107

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The pharmacological modification of dopamine transmission has long been employed as a therapeutic tool in the treatment of many mental health disorders. However, as many of the pharmacotherapies today are not without significant side effects, or they alleviate only a particular subset of symptoms, the identification of novel therapeutic targets is imperative. In light of these challenges, the recognition that dopamine receptors can form heteromers has significantly expanded the range of physiologically relevant signaling complexes as well as potential drug targets. Furthermore, as the physiology and disease relevance of these receptor heteromers is further understood, their ability to exhibit pharmacological and functional properties distinct from their constituent receptors, or modulate the function of endogenous homomeric receptor complexes, may allow for the development of alternate therapeutic strategies and provide new avenues for drug design. In this review, we describe the emerging neurobiology of the known dopamine receptor heteromers, their physiological relevance in brain, and discuss the potential role of these receptor complexes in neuropsychiatric disease. We highlight their value as targets for future drug development and discuss innovative research strategies designed to selectively target these dopamine receptor heteromers in the search for novel and clinically efficacious pharmacotherapies.

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Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Cited by 207 publications

References 41 publications

Dopaminergic signaling in dendritic spines

Dopaminergic signaling in dendritic spines

Dendritic distributions of dopamine D1 receptors in the rat nucleus accumbens are synergistically affected by startle-evoking auditory stimulation and apomorphine

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

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