Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation

Donthamsetti, Prashant; Gallo, Eduardo F.; Buck, David C.; Stahl, Edward L.; Zhu, Ying; Lane, J. Robert; Bohn, Laura M.; Neve, Kim A.; Kellendonk, Christoph; Javitch, Jonathan A.

doi:10.1038/s41380-018-0212-4

Cited by 59 publications

(69 citation statements)

References 82 publications

(104 reference statements)

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“…PAC1-hop1 was also shown to regulate Ca 2+ mobilization and neurosecretion 43–46 . Such differential signal transduction could affect behavioral phenotypes, as previously demonstrated for other GPCRs 47–50 . Accordingly, we have previously shown in adult mice that acute foot-shock stressor induces a change in the ratio between PAC1-hop and PAC1-null splice isoforms in the hypothalamic paraventricular nucleus 4 .…”

Section: Discussionsupporting

confidence: 55%

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Biran

Gliksberg

Shirat

et al. 2020

Preprint

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25The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as 26 ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of 27 stress response in general. Alternative splicing of PAC1 results in multiple gene 28 products, which differ in their mode of signalling and tissue distribution. However, 29 the roles of distinct splice variants in the regulation of stress behavior is poorly 30 understood. Alternative splicing of a short exon, which is known as the "hop 31 cassette", occurs during brain development and in response to stressful challenges. To 32 examine the function of this variant, we generated a splice-specific zebrafish mutant 33 lacking the hop cassette, which we designated 'hopless'. We show that hopless mutant 34 larvae display increased anxiety-like behavior, including reduced dark exploration and 35 impaired habituation to dark exposure. Conversely, adult hopless mutants displayed 36 superior ability to rebound from an acute stressor, as they exhibited reduced anxiety-37 like responses to an ensuing novelty stress. We propose that the developmental loss of 38 a specific PAC1 splice variant mimics prolonged mild stress exposure, which in the 39 long term, predisposes the organism's stress response towards a resilient phenotype. 40Our study presents a unique genetic model demonstrating how early-life state of 41 anxiety paradoxically correlates with reduced stress susceptibility in adulthood. 42 43 44 45 46 47 48 49 50 51 52 53 PAC1 (a.k.a. Adcyap1r1) is a G-protein coupled receptor (GPCR) that serves as the 54 high-affinity receptor for pituitary adenylate cyclase-activating polypeptide (PACAP). 55 PAC1 has pleiotropic functions and was demonstrated to be involved in the regulation 56 of several homeostatic processes including metabolic rate and food consumption 1,2 , 57 circadian rhythm 3 and, in particular, stress response 4,5 . Intracerebroventricular injection 58 of PACAP increased phosphorylated cyclic AMP response element binding protein 59(pCREB) and CRH immunoreactivity in the rat paraventricular nucleus 6 . PACAP 60 knockout mice display blunted hypothalamic CRH levels in response to restraint 61 challenge 7 . PACAP/PAC1 signaling was also associated with hypothalamo-pituitary-62 adrenal activity and stress-related behaviors in humans and rodents 5,8,9 . Furthermore, 63 this pathway was correlated with stress-related risky behaviors in human and 64 rodents 10,11 . Overall, these findings support positive stress regulation by PAC1; yet, 65 some data suggest that it may also act to suppress stress phenotypes 4,12 . 66It has been suggested that genetic vulnerability to post-traumatic stress disorder 67 (PTSD) may depend on PAC1 expression and single-nucleotide polymorphism (SNP) 68 in the PAC1 gene. Ressler et al. demonstrated that a specific PAC1 genotype is strongly 69 correlated with susceptibility to PTSD in women, probably due to perturbed expression 70 of PAC1 resulting in impaired stress responses 13 . The same PAC1 SNP was associat...

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Section: Discussionsupporting

confidence: 55%

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Biran

Gliksberg

Shirat

et al. 2020

Preprint

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“…D2R upregulation in iSPNs enhances this modulation by dopamine and D2R-OENAcInd mice show 48 decreased baseline synaptic transmission as well as an enhancement in inhibition of synaptic transmission by 49 after activation of D2R with an agonist (Gallo et al, 2018). This could be measured via slice physiology at intra-50 striatal collaterals to the direct pathway and the canonical projections to the ventral pallidum (Gallo et al, 2018). 51 A follow up in vivo physiological analysis showed that the effects of disinhibition in D2R-OENAcInd mice are mostly 52 measurable at the level of the striato-pallidal synapse (Gallo et al, 2018).…”

Section: Introduction: 29mentioning

confidence: 99%

“…Pharmacological studies have uncovered an important role for 31 dopamine receptors in the Nucleus accumbens (NAc) in the regulation of incentive motivation and the willingness 32 to work for reward (Aberman, Ward, & Salamone, 1998;Berridge, 2007;Salamone, Correa, Farrar, & Mingote, 33 2007). In this context dopamine is thought to regulate effort-related processes that are important to overcome 34 work-related response costs rather than to adapt the animals response to changes in reward value (Filla et (iSPNs) projection neurons (D2R-OENAcInd mice) is sufficient to enhance motivation, whereas upregulation in 41 cholinergic interneurons (D2R-OEChAT mice), which also express D2Rs had no effect on progressive ratio 42 performance (Gallo et al, 2018) (Note, that for simplicity we are using the term indirect pathway, which may 43 have its limitations in the (Kupchik et al, 2015). 44…”

Section: Introduction: 29mentioning

confidence: 99%

“…D2Rs in iSPNs are transported to axonal terminals, where they reduce inhibitory transmission at intra-45 striatal collaterals and striato-pallidal synapses (Cooper & Stanford, 2001;Dobbs et al, 2016;Floran, Floran, 46 Sierra, & Aceves, 1997; Kohnomi, Koshikawa, & Kobayashi, 2012; Tecuapetla, Koos, Tepper, Kabbani, & 47 Yeckel, 2009). D2R upregulation in iSPNs enhances this modulation by dopamine and D2R-OENAcInd mice show 48 decreased baseline synaptic transmission as well as an enhancement in inhibition of synaptic transmission by 49 after activation of D2R with an agonist (Gallo et al, 2018). This could be measured via slice physiology at intra-50 striatal collaterals to the direct pathway and the canonical projections to the ventral pallidum (Gallo et al, 2018).…”

Section: Introduction: 29mentioning

confidence: 99%

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Dopamine D2R upregulation in nucleus accumbens indirect pathway does not affect Pavlovian or Go/No-Go Learning

Martyniuk

Dandeneau

Balsam

et al. 2020

Preprint

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16Ventral striatal dopamine is thought to be important for associative learning. Dopamine exerts its role via 17 activation of dopamine D1 and D2 receptors in the ventral striatum. Upregulation of dopamine D2R in the indirect 18 pathway of the nucleus accumbens (NAc) impairs incentive motivation via inhibiting synaptic transmission to the 19 ventral pallidum. Here, we determined whether upregulation of D2Rs and the resulting impairment in indirect 20 pathway function modulates associative learning in an auditory Pavlovian reward learning task as well as Go learning in an operant based reward driven Go/No-Go task. We found that upregulation of D2Rs in indirect 22

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“…At the μ-opioid receptor G protein signaling has been proposed to be responsible for analgesia, with side effects such as respiratory depression resulting from arrestin-mediated signaling (2,3), although this paradigm has recently been challenged (4)(5)(6). We have demonstrated that β-arrestin recruitment to the dopamine D2 receptor in indirect pathway neurons in the ventral striatum leads to enhanced locomotion, whereas G protein signaling is necessary for incentive behavior (7), further emphasizing the potential importance of biased signaling in more targeted therapeutics.…”

Section: Introductionmentioning

confidence: 90%

A novel luminescence-based β-arrestin membrane recruitment assay for unmodified GPCRs

Pedersen

Pham²,

Mancebo³

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) signal through activation of G proteins and subsequent modulation of downstream effectors. More recently, G protein-independent signaling via the arrestin pathway has also been implicated in important physiological functions. This has led to great interest in the identification of biased ligands that favor either the G protein or arrestin-signaling pathways. Currently available screening techniques that measure arrestin recruitment have required C-terminal receptor modifications that can in principle alter protein interactions and thus signaling. Here, we have developed a novel luminescence-based assay to measure arrestin recruitment to any unmodified receptor.NanoLuc, an engineered luciferase from ophlorus gracilirostris (deep sea shrimp), is smaller and brighter than other well-established luciferases. Recently, several publications have explored functional NanoLuc split sites for use in complementation assays. Here, we have identified a novel split site and have fused the N-terminal fragment to a membrane tether and the C-terminal fragment to the N-terminus of either β-arrestin 1 or 2. Upon receptor activation, arrestin is recruited to the plasma membrane in an agonist concentrationdependent manner and the two NanoLuc fragments complement to reconstitute functional luciferase, which allows quantification of recruitment with a single luminescence signal. Our assay avoids potential artifacts related to C-terminal receptor modification. The split NanoLuc arrestin recruitment assay has promise as a new generic assay for measuring arrestin recruitment to diverse GPCR types in heterologous or native cells.

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Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation

Cited by 59 publications

References 82 publications

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Dopamine D2R upregulation in nucleus accumbens indirect pathway does not affect Pavlovian or Go/No-Go Learning

A novel luminescence-based β-arrestin membrane recruitment assay for unmodified GPCRs

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