Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs, Nikhil M.; Snyder, Joshua C.; Jacobsen, Jacob P. R.; Peterson, Sean M.; Caron, Marc G.

doi:10.1073/pnas.1215489109

Cited by 82 publications

(98 citation statements)

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“…β-arrestin 2 knockout mice provided robust behavioral and biochemical evidence for a critical D 2 R/β-arrestin signaling pathway in the striatum (10). Furthermore, neuronal selective deletion of GSK3β, a putative D 2 R/β-arrestin 2 effector, could reproduce the pharmacological blockade of D 2 Rs with antipsychotics (11). Although these studies suggest that D 2 Rs, like many other GPCRs, use pleiotropic signaling pathways to mediate their effects, the brain DA system is uniquely complex, as diverse responses may also rely upon many other determinants.…”

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confidence: 97%

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Peterson¹,

Pack²,

Wilkins

et al. 2015

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

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The neuromodulator dopamine signals through the dopamine D2 receptor (D 2 R) to modulate central nervous system functions through diverse signal transduction pathways. D 2 R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D 2 R signals through distinct G-protein and β-arrestin pathways, and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D 2 R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D 2 R mutants with strongly biased signal transduction for either the G-protein or β-arrestin interactions. These mutants were used to resolve the role of G proteins and β-arrestins in D 2 R signaling assays. The results show that D 2 R interactions with the two downstream effectors are dissociable and that G-protein signaling accounts for D 2 R canonical MAP kinase signaling cascade activation, whereas β-arrestin only activates elements of this cascade under certain conditions. Nevertheless, when expressed in mice in GABAergic medium spiny neurons of the striatum, the β-arrestin-biased D 2 R caused a significant potentiation of amphetamine-induced locomotion, whereas the G proteinbiased D 2 R had minimal effects. The mutant receptors generated here provide a molecular tool set that should enable a better definition of the individual roles of G-protein and β-arrestin signaling pathways in D 2 R pharmacology, neurobiology, and associated pathologies.

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confidence: 97%

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Peterson¹,

Pack²,

Wilkins

et al. 2015

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

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“…for chronic experiments) to induce acute DA-depletion (DDD) and parkinsonian symptoms such as akinesia. Following AMPT injection for 1 h, DDD mice were injected with L-DOPA (25 mg/kg, s.c.) and benserazide (12.5 mg/kg, s.c.) and activity was recorded in an Accuscan activity monitor (Accuscan Instruments) as described previously (16,66). Total distance traveled (forward locomotion) and vertical activity (dyskinesia) were measured at 5-min intervals and data were analyzed in 5-min increments for 120 min.…”

Section: Animalsmentioning

confidence: 99%

“…Western blot analyses were performed on mice upon completion of behavioral analyses (66). Briefly, striatum was rapidly dissected from mouse brains on ice and tissue samples were immediately lysed in ice-cold RIPA buffer solution.…”

Section: Animalsmentioning

confidence: 99%

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

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

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105

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Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

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“…15 In addition, all mouse lines were crossed to a Rosa26-stop-EYFP reporter mouse line 16 obtained from The Jackson laboratory (B6.129X1-Gt(ROSA)26Sor tm1(EYFP)Cos /J) to confirm the expression pattern of all the Cre lines and to confirm deletion of GSK3b in specific neurons. 17 The b-arrestin1 (barr1; C57Bl6) and b-arr2 (C57/129 mix) knockout mice have been described previously. 18,19 Amphetamine (Amph) and morphine (Sigma, St Louis, MO) were dissolved in saline (Sal).…”

Section: Animals and Drugsmentioning

confidence: 99%

The physiological relevance of functional selectivity in dopamine signalling

Urs

Caron

2014

Int J Obes Supp

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We sought to determine the role of functionally selective dopamine (DA) signalling pathways (G protein or b-arrestin) in DA-dependent behaviours. Mice that were globally deficient for b-arrestins or mice deficient in GSK3b in D2 receptor (D2R)-expressing neurons were used to investigate the role of functional selectivity in DA-dependent behaviours such as locomotor activity and conditioned place preference (CPP). Wild-type or knockout mice were injected with drugs such as morphine and amphetamine, which are known to increase DA levels in the brain and to induce a hyper-locomotor response and CPP. Unlike b-arrestin1 (barr1)-deficient mice, mice globally deficient for b-arrestin2 (barr2) mount a reduced hyperlocomotor response to either morphine or amphetamine. However, mice deficient in GSK3b in D2R-expressing neurons show a significantly reduced locomotor response to only amphetamine but not morphine. Interestingly, all mice tested show a normal CPP response to either morphine or amphetamine. b-arrestin-mediated DA receptor signalling has an important role in the locomotor response, but not CPP, to drugs such as morphine and amphetamine, demonstrating a functional selectivity of DA-dependent behaviours in mice. It is likely that G-protein-dependent signalling through DA receptors mediates the CPP response.

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Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Cited by 82 publications

References 59 publications

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

The physiological relevance of functional selectivity in dopamine signalling

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