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LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1.

ABSTRACT: Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT_2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, without effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and βArr1-KO animals. By contrast, in βArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs, but not in βArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in βArr1-KOs. Collectively, these results reveal that LSD's psychedelic drug-like actions appear to require βArr2.

SUBMITTER: Rodriguiz RM

PROVIDER: S-EPMC8417039 | biostudies-literature |

REPOSITORIES: biostudies-literature

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beta-arrestin-2 deficiency effect on intestinal tumorigenesis in Apc-mutated mice

Project description:Amoung their pleiotropic functions, a role was recently assigned for b-arrestin scaffold proteins in tumor growth, angiogenesis and invasion. In order to elucidate the roles of b-arrestins in tumour developement in intestinal epithelium initiated by Apc mutation, we determined the effects of b-arrestin gene deletion on intestinal polypolis using ApcD14/+ mice, a relevant mouse model of human intestinal tumorigenesis.Here we show that unlike b-arrestin1, absence of b-arrestin2 dramatically decreased the number of spontaneously developping intestinal tumors in ApcD14/+ mice.The size of residual tumors was similarto that of controls, suggesting that their growth is b-arrestin2-independent. This result demonstrated a role for b-arrestin2 in the early development of a tumor subset. Gene expression profils analysis of ApcD14/+:Arrb2+/+ and ApcD14/+:Arrb2-/- tumors showed two distinct clusters among ApcD14/+:Arrb2+/+ tumors and one of them was statistically more correlated to ApcD14/+:Arrb2-/- tumors than to the other ApcD14/+:Arrb2+/+ cluster, eventhough a number of genes saw their expression affected in ApcD14/+:Arrb2-/- tumors only. Altogether, our data unravel an unexpected early diversity among intestinal tumors and a crucial role for b-arrestin2 in early tumor development in Apc-mutated mice. 16 tumors from ApcD14/+:Arrb2+/+ mice and 13 tumors from ApcD14/+:Arrb2-/- mice

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Beta-arrestin scaffolding of phosphatidylinositol 4-phosphate 5-kinase Ialpha promotes agonist-stimulated sequestration of the beta2-adrenergic receptor.

Project description:Members of the seven-transmembrane receptor (7TMR) superfamily are sequestered from the plasma membrane following stimulation both to limit cellular responses as well as to initiate novel G protein-independent signaling pathways. The best studied mechanism for 7TMR internalization is via clathrin-coated pits, where clathrin and adaptor protein complex 2 nucleate and polymerize upon encountering the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP(2)) to form the outer layer of the clathrin-coated vesicle. Activated receptors are recruited to clathrin-coated pits by beta-arrestins, scaffolding proteins that interact with agonist-occupied 7TMRs as well as adaptor protein complex 2 and clathrin. We report here that following stimulation of the beta2-adrenergic receptor (beta2-AR), a prototypical 7TMR, beta-arrestins bind phosphatidylinositol 4-phosphate 5-kinase (PIP5K) Ialpha, a PIP(2)-producing enzyme. Furthermore, beta-arrestin2 is required to form a complex with PIP5K Ialpha and agonist-occupied beta2-AR, and beta-arrestins synergize with the kinase to produce PIP(2) in response to isoproterenol stimulation. Interestingly, beta-arrestins themselves bind PIP(2), and a beta-arrestin mutant deficient in PIP(2) binding no longer internalizes 7TMRs, fails to interact with PIP5K Ialpha, and is not associated with PIP kinase activity assayed in vitro. However, a chimeric protein in which the core kinase domain of PIP5K Ialpha has been fused to the same beta-arrestin mutant rescues internalization of beta2-ARs. Collectively, these data support a model in which beta-arrestins direct the localization of PIP5K Ialpha and PIP(2) production to agonist-activated 7TMRs, thereby regulating receptor internalization.

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