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β-Arrestin-biased signaling mediates memory reconsolidation.

ABSTRACT: A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates β-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of β1-adrenergic β-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. β-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain β-adrenergic Gs protein- and β-arrestin-dependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the β-arrestin/ERK signaling by the biased β-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of β-arrestin2 in the entorhinal cortex of β-arrestin 2-deficient mice rescues β1-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that β-arrestin-biased signaling regulates memory reconsolidation and reveal the potential for β-arrestin-biased ligands in the treatment of memory-related disorders.

SUBMITTER: Liu X

PROVIDER: S-EPMC4394255 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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β-Arrestin-biased signaling mediates memory reconsolidation.

Liu Xing X Ma Li L Li Hao Hong HH Huang Bing B Li You Xing YX Tao Ye Zheng YZ Ma Lan L

Proceedings of the National Academy of Sciences of the United States of America 20150323 14

A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates β-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of β1-adrenergic β-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. β-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, an ...[more]

PMID: 25831532

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Project description:Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo. Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s). Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a β2AR- and βarr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on βarr-dependent β2AR signaling. Conclusion: Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits.

Project description:BackgroundBiased agonism of the angiotensin II receptor is known to promote cardiac contractility. Our laboratory indicated that these effects may be attributable to changes at the level of the myofilaments. However, these signaling mechanisms remain unknown. Because a common finding in dilated cardiomyopathy is a reduction in the myofilament-Ca2+ response, we hypothesized that β-arrestin signaling would increase myofilament-Ca2+ responsiveness in a model of familial dilated cardiomyopathy and improve cardiac function and morphology.MethodsWe treated a dilated cardiomyopathy-linked mouse model expressing a mutant tropomyosin (Tm-E54K) for 3 months with either TRV120067, a β-arrestin 2-biased ligand of the angiotensin II receptor, or losartan, an angiotensin II receptor blocker. At the end of the treatment protocol, we assessed cardiac function using echocardiography, the myofilament-Ca2+ response of detergent-extracted fiber bundles, and used proteomic approaches to understand changes in posttranslational modifications of proteins that may explain functional changes. We also assessed signaling pathways altered in vivo and by using isolated myocytes.ResultsTRV120067- treated Tm-E54K mice showed improved cardiac structure and function, whereas losartan-treated mice had no improvement. Myofilaments of TRV120067-treated Tm-E54K mice had significantly improved myofilament-Ca2+ responsiveness, which was depressed in untreated Tm-E54K mice. We attributed these changes to increased MLC2v and MYPT1/2 phosphorylation seen only in TRV120067-treated mice. We found that the functional changes were attributable to an activation of ERK1/2-RSK3 signaling, mediated through β-arrestin, which may have a novel role in increasing MLC2v phosphorylation through a previously unrecognized interaction of β-arrestin localized to the sarcomere.ConclusionsLong-term β-arrestin 2-biased agonism of the angiotensin II receptor may be a viable approach to the treatment of dilated cardiomyopathy by not only preventing maladaptive signaling, but also improving cardiac function by altering the myofilament-Ca2+ response via β-arrestin signaling pathways.

Project description:RationaleMicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize β-adrenergic receptor (βAR) signaling, β-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the β-arrestin-biased βAR ligand carvedilol, we previously showed that β-arrestin1 (not β-arrestin2)-biased β1AR (not β2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes β-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1.ObjectiveHere, we investigate whether β-arrestin-mediated βAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling.Methods and resultsIn mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a β-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2ARs and β1ARs, respectively. Mechanistically, β-arrestin 1 or 2 regulates maturation of three newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of β-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, β-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets.ConclusionsOur findings indicate a novel role for βAR-mediated β-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.

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β-Arrestin-biased signaling mediates memory reconsolidation.

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β-Arrestin-biased signaling mediates memory reconsolidation.

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