β2-adrenergic receptor transcriptional response in HEK293 wild type, β-arrestin1/2 KO and Gαs KO cells upon isoproterenol stimulation.
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PROVIDER: PRJNA1027499 | ENA |
REPOSITORIES: ENA
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Project description:The role of nuclear signaling by β2-adrenergic receptor (β2AR) through β-arrestins in the absence of a functional Gαs protein has not been evaluated. This has prevented a comprehensive understanding of the relative contribution of Gαs and β-arrestins to the overall β2AR signaling, thereby limiting our appreciation of how β-arrestin- or Gαs-biased ligands may affect their therapeutic outcomes. To explore the role of Gαs and β-arrestin in nuclear transcriptional programs in a global unbiased approach, we performed RNA sequencing studies in cells lacking either of these two signaling arms downstream from β2AR, followed by detailed bioinformatics analysis of gene expression signatures. We noticed multiple genes whose individual expression levels were distinct in β-arrestin1/2 and Gαs KO cells. Rather than focusing on the individual gene level, we performed a detailed analysis of gene signatures taking advantage of large datasets that were recently compiled as part of the Molecular Signatures Database (MSigDB). This approach supported that β-arrestins are not required for the activation of PKA gene signatures, including prior datasets of forskolin and CREB1 targets, while Gαs is essential. β2AR activation also led to significant changes in multiple MAPK signatures, which clearly support the activation of MAPK nuclear transcriptional programs by these receptors. Although individual variations do exist reflecting the complexities of β-arrestin- and Gαs-mediated signaling events, stimulation of these MAPK regulated gene signatures was not significantly reduced in β-arrestin1/2 KO cells but abolished in Gαs KO cells.
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