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Genetic evidence that ?-arrestins are dispensable for the initiation of ?2-adrenergic receptor signaling to ERK.

ABSTRACT: The ?2-adrenergic receptor (?2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that ?-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of ?-arrestin 1 (?-arr1) and ?-arr2 in ?2AR internalization, trafficking, and signaling to ERK. We found that only ?-arr2 was essential for ?2AR internalization. Unexpectedly, ?-arr1 and ?-arr2 and receptor internalization were dispensable for ERK activation. Instead, ?2AR signaled through G?s and G?? subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for ?2AR signaling through ?-arrestin-independent pathways in key physiological functions and under pathological conditions.

SUBMITTER: O'Hayre M

PROVIDER: S-EPMC5751434 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Genetic evidence that β-arrestins are dispensable for the initiation of β2-adrenergic receptor signaling to ERK.

O'Hayre Morgan M Eichel Kelsie K Avino Silvia S Zhao Xuefeng X Steffen Dana J DJ Feng Xiaodong X Kawakami Kouki K Aoki Junken J Messer Karen K Sunahara Roger R Inoue Asuka A von Zastrow Mark M Gutkind J Silvio JS

Science signaling 20170620 484

The β2-adrenergic receptor (β2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We fou ...[more]

PMID: 28634209

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Project description:ObjectiveNeuroimmune interactions between the sympathetic nervous system (SNS) and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue. It has been proposed that the SNS maintains adipose tissue macrophages (ATMs) in an anti-inflammatory state via direct norepinephrine (NE) signaling to macrophages. This study aimed to investigate the physiological importance of this paradigm by utilizing a mouse model in which the adrenergic signaling from the SNS to macrophages, but not to other adipose tissue cells, was disrupted.MethodsWe generated a macrophage-specific B2AR knockout mouse (Adrb2ΔLyz2) by crossing Adrb2fl/fl and Lyz2Cre/+ mice. We have previously shown that macrophages isolated from Adrb2ΔLyz2 animals do not respond to NE stimulation in vitro. Herein we performed a metabolic phenotyping of Adrb2ΔLyz2 mice on either chow or high-fat diet (HFD). We also assessed the adipose tissue function of Adrb2ΔLyz2 animals during fasting and cold exposure. Finally, we transplanted Adrb2ΔLyz2 bone marrow to low-density lipoprotein receptor (LDLR) knockout mice and investigated the development of atherosclerosis during Western diet feeding.ResultsWe demonstrated that SNS-associated ATMs have a transcriptional profile indicative of activated beta-2 adrenergic receptor (B2AR), the main adrenergic receptor isoform in myeloid cells. However, Adrb2ΔLyz2 mice have unaltered energy balance on a chow or HFD. Furthermore, Adrb2ΔLyz2 mice show similar levels of adipose tissue inflammation and function during feeding, fasting, or cold exposure, and develop insulin resistance during HFD at the same rate as controls. Finally, macrophage-specific B2AR deletion does not affect the development of atherosclerosis on an LDL receptor-null genetic background.ConclusionsOverall, our data suggest that the SNS does not directly modulate the phenotype of adipose tissue macrophages in either lean mice or mouse models of cardiometabolic disease. Instead, sympathetic nerve activity exerts an indirect effect on adipose tissue macrophages through the modulation of adipocyte function.

Dataset Information

Genetic evidence that ?-arrestins are dispensable for the initiation of ?2-adrenergic receptor signaling to ERK.

Publications

Genetic evidence that β-arrestins are dispensable for the initiation of β<sub>2</sub>-adrenergic receptor signaling to ERK.

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