Dopamine D1Receptor Signaling: Does GαQ–Phospholipase C Actually Play a Role?

Lee, Sang Min; Yang, Yang; Mailman, Richard B.

doi:10.1124/jpet.114.214411

Cited by 28 publications

(23 citation statements)

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“…This compound has been used extensively for investigations of the D1R and has a complicated pharmacological history (reviewed in ref 41). It has variously been reported as a D1R agonist or antagonist for stimulating cAMP accumulation but has also been described as a biased agonist for stimulating PLC β activity and mobilizing Ca 2+ (see ref 41 and references cited therein). This hypothesis has recently undergone revision to suggest that SKF83959 is a D1R–D2R dimer-selective agonist, where the D1R–D2R dimer is selectively linked to PLC β activation and Ca 2+ mobilization (ref 38 and references cited therein).…”

Section: Resultsmentioning

confidence: 99%

“…We also observed that SKF83959 was a somewhat promiscuous ligand that exhibited moderate affinity for a number of GPCRs. 39 On the basis of these and other data, Mailman and colleagues 40,41 have suggested that SKF83959 is not a PLC β -biased agonist at the D1R, or a D1R–D2R dimer-selective agonist, but simply a partial D1R agonist that exhibits a number of behavioral effects caused by off-target activity at other GPCRs. In support of this hypothesis is the observation that in D1R knockout mice, “D1-selective” stimulation of PLC β is still observed 63 and that in adult rodents D1R–D2R dimers are either nonexistent or expressed at extremely low levels.…”

Section: Resultsmentioning

confidence: 99%

“…36 Indeed, SKF83959 has been proposed as a prototypical D1–D2 receptor dimer-selective agonist. 37,38 However, the selectivity of SKF83959 for either D1–D2 receptor dimers or D1 receptor-mediated PLC β signaling has recently come under question 39,40 (for a review, see ref 41). The possibility that the effects of SKF83959 on PLC β -mediated signaling may not be mediated by D1Rs, or D1–D2 receptor dimers, but rather by interactions with other GPCRs or signaling proteins has been raised.…”

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confidence: 99%

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Identification of G Protein-Biased Agonists That Fail To Recruit β-Arrestin or Promote Internalization of the D1 Dopamine Receptor

Conroy

Free

Sibley

2015

ACS Chem. Neurosci.

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The D1 dopamine receptor (D1R) has been implicated in numerous neuropsychiatric disorders, and D1R-selective ligands have potential as therapeutic agents. Previous studies have identified substituted benzazepines as D1R-selective agonists, but the in vivo effects of these compounds have not correlated well with their in vitro pharmacological activities. A series of substituted benzazepines, and structurally dissimilar D1R-selective agonists, were tested for their functional effects on D1R-mediated cAMP accumulation, D1R-promoted β-arrestin recruitment, and D1R internalization using live cell functional assays. All compounds tested elicited an increase in the level of cAMP accumulation, albeit with a range of efficacies. However, when the compounds were evaluated for β-arrestin recruitment, a subset of substituted benzazepines, SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670, failed to activate this pathway, whereas the others showed similar activation efficacies as seen with cAMP accumulation. When tested as antagonists, the five biased compounds all inhibited dopamine-stimulated β-arrestin recruitment. Further, D1R internalization assays revealed a corroborating pattern of activity in that the G protein-biased compounds failed to promote D1R internalization. Interestingly, the biased signaling was unique for the D1R, as the same compounds were agonists of the related D5 dopamine receptor (D5R), but revealed no signaling bias. We have identified a group of substituted benzazepine ligands that are agonists at D1R-mediated G protein signaling, but antagonists of D1R recruitment of β-arrestin, and also devoid of agonist-induced receptor endocytosis. These data may be useful for interpreting the contrasting effects of these compounds in vitro versus in vivo, and also for the understanding of pathway-selective signaling of the D1R.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of G Protein-Biased Agonists That Fail To Recruit β-Arrestin or Promote Internalization of the D1 Dopamine Receptor

Conroy

Free

Sibley

2015

ACS Chem. Neurosci.

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“…More recently, it has been recognized that drugs may cause differential activation of signaling pathways modulated by a single receptor, a mechanism termed functional selectivity or biased signaling (Urban et al, 2007). There are numerous studies showing that D 1 selective ligands can evoke this mechanism, although there is some controversy about its nature (Lee et al, 2014). The specific signaling properties may, therefore, influence the clinical effects.…”

Section: Intrinsic Pharmacological Issuesmentioning

confidence: 99%

D₁, not D₂, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

Mailman

Yang

Huang

2020

Preprint

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Levodopa is the Parkinson’s disease standard-of-care, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral “dopamine agonist” matches the efficacy of levodopa. Although there are consistent data in both primate models and in Parkinson’s disease showing that selective high intrinsic activity D1 agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson’s patients.

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“…To gain insight into initial signalling modes by which auditory-cortical D1/D5 receptors might control memory-relevant proteome changes, a second screen was performed utilising SKF83959. This agonist was reported to antagonise dopamine-mediated stimulation of ADCY and to preferentially activate PLC [ 26 , 27 ] (but see [ 28 ]). Differential regulation of selected proteins was validated by immunoblot analysis and/or immunocytochemical studies on primary cultured neurons.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of dopamine signalling on long-term memory formation and consolidation in rodent brain

et al. 2015

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BackgroundUsing auditory discrimination learning in gerbils, we have previously shown that activation of auditory-cortical D1/D5 dopamine receptors facilitates mTOR-mediated, protein synthesis-dependent mechanisms of memory consolidation and anterograde memory formation. To understand molecular mechanisms of this facilitatory effect, we tested the impact of local pharmacological activation of different D1/D5 dopamine receptor signalling modes in the auditory cortex. To this end, protein patterns in soluble and synaptic protein-enriched fractions from cortical, hippocampal and striatal brain regions of ligand- and vehicle-treated gerbils were analysed by 2D gel electrophoresis and mass spectrometry 24 h after intervention.ResultsAfter auditory-cortical injection of SKF38393 – a D1/D5 dopamine receptor-selective agonist reported to activate the downstream effectors adenylyl cyclase and phospholipase C – prominent proteomic alterations compared to vehicle-treated controls appeared in the auditory cortex, striatum, and hippocampus, whereas only minor changes were detectable in the frontal cortex. In contrast, auditory-cortical injection of SKF83959 – a D1/D5 agonist reported to preferentially stimulate phospholipase C – induced pronounced changes in the frontal cortex. At the molecular level, we detected altered regulation of cytoskeletal and scaffolding proteins, changes in proteins with functions in energy metabolism, local protein synthesis, and synaptic signalling. Interestingly, abundance and/or subcellular localisation of the predominantly presynaptic protein α-synuclein displayed dopaminergic regulation. To assess the role of α-synuclein for dopaminergic mechanisms of memory modulation, we tested the impact of post-conditioning systemic pharmacological activation of different D1/D5 dopamine receptor signalling modes on auditory discrimination learning in α-synuclein-mutant mice. In C57BL/6JOlaHsd mice, bearing a spontaneous deletion of the α-synuclein-encoding gene, but not in the related substrains C57BL/6JCrl and C57BL/6JRccHsd, adenylyl cyclase-mediated signalling affected acquisition rates over future learning episodes, whereas phospholipase C-mediated signalling affected final memory performance.ConclusionsDopamine signalling modes via D1/D5 receptors in the auditory cortex differentially impact protein profiles related to rearrangement of cytomatrices, energy metabolism, and synaptic neurotransmission in cortical, hippocampal, and basal brain structures. Altered dopamine neurotransmission in α-synuclein-deficient mice revealed that distinct D1/D5 receptor signalling modes may control different aspects of memory consolidation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12953-015-0069-2) contains supplementary material, which is available to authorized users.

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Dopamine D₁Receptor Signaling: Does Gα_Q–Phospholipase C Actually Play a Role?

Cited by 28 publications

References 99 publications

Identification of G Protein-Biased Agonists That Fail To Recruit β-Arrestin or Promote Internalization of the D1 Dopamine Receptor

Identification of G Protein-Biased Agonists That Fail To Recruit β-Arrestin or Promote Internalization of the D1 Dopamine Receptor

D₁, not D₂, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

Differential effects of dopamine signalling on long-term memory formation and consolidation in rodent brain

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Dopamine D1Receptor Signaling: Does GαQ–Phospholipase C Actually Play a Role?

Cited by 28 publications

References 99 publications

Identification of G Protein-Biased Agonists That Fail To Recruit β-Arrestin or Promote Internalization of the D1 Dopamine Receptor

Identification of G Protein-Biased Agonists That Fail To Recruit β-Arrestin or Promote Internalization of the D1 Dopamine Receptor

D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

Differential effects of dopamine signalling on long-term memory formation and consolidation in rodent brain

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Dopamine D₁Receptor Signaling: Does Gα_Q–Phospholipase C Actually Play a Role?

D₁, not D₂, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa