Chapter Seventeen - Systems Analysis of Arrestin Pathway Functions
Section snippets
G Protein-Coupled Receptor Signaling Activity
G protein-coupled receptor (GPCR)-mediated signaling represents one of the most fundamental physiological processes. GPCR signaling has been demonstrated to regulate almost all forms of cellular communication, while utilizing an incredibly diverse series of functional mechanisms to do so.1 As GPCR biology regulates the vast majority of physiological processes, it is unsurprising that nearly half of all current pharmacotherapeutics target this class of proteins.2 Historically, therapeutic agents
Signaling Diversity Among GPCRs
Aided by advances in technology and receptor theory development, our current appreciation of the multiple molecular nuances in GPCR signaling has expanded dramatically.18, 19, 20 Despite their G protein-biased description, their resultant spectrum of signaling output is unlikely to be solely G protein dependent. Multiple avenues of investigation have shown that GPCR cellular signaling exhibits considerably greater diversity and texture than previously appreciated.17, 21, 22 As we have
Systems Analysis of Receptor Signaling Systems
The field of GPCR signal transduction over the past decade has begun to efficiently and productively interact with the mass data analytical realms of genomic, proteomic, and metabolomic analyses.20 The consideration of the nature of signal transduction systems has moved away from linear signaling cascades, controlled by “Brownian” modes of motion of individual signaling factors, to preorganized encrypton-mediated signaling paradigms.81 We, therefore, consider that GPCR signaling systems possess
Functional Analyses of Arrestin Signaling Paradigms
We have so far described how the initial discovery of β-arrestin-mediated GPCR signaling activity was able to uncover an entirely new era of receptor signaling.30 The demonstration that the “desensitized” GPCR was indeed still active revealed the presence of a previously unseen spectrum of GPCR signaling activity. As with many paradigm-creating discoveries, it has taken nearly a decade for this concept to reach the level of common acceptance and translational therapeutic development.26, 83 At
Conclusions
The demonstration that β-arrestin-regulated signaling pathways emanate from GPCRs represented a significant shift, not just for cell signaling research, but for our understanding of the diversity of signaling systems and for the rational design of selective, discrete therapeutics. Rather than considering signaling systems as linear pathways composed of a simple sequence of kinases and substrates, applying a systems-level investigation has led to the appreciation that GPCR signaling engenders
Acknowledgments
This work was supported by the Intramural Program of the National Institute on Aging and National Institutes of Health.
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Cited by (14)
Systems Pharmacology: Enabling Multidimensional Therapeutics
2022, Comprehensive PharmacologyAging-related modifications to G protein-coupled receptor signaling diversity
2021, Pharmacology and TherapeuticsCitation Excerpt :These mice lacked both β-arrestin2-dependent desensitization of PTH-activated G proteins and β-arrestin2-mediated signaling. Groundbreaking in cellula and in vivo research focusing on the type I parathyroid hormone receptor (PTH1R) has shown that there is a stable and reliable difference in clinically-relevant complex transcriptional signaling patterns between experimental ligands that demonstrate β-arrestin-biased or G protein coupling (Gesty-Palmer et al., 2006, 2013; Gesty-Palmer and Luttrell, 2011; Maudsley et al., 2013, 2015; Luttrell et al., 2018). In these studies a β-arrestin-dependent agonist, D-Trp12, Tyr34-bovinePTH (7–34) (PTH-βarr), was employed in multiple molecular assays.
Translating in vitro ligand bias into in vivo efficacy
2018, Cellular SignallingCitation Excerpt :Moreover, the transcriptomic fingerprint of [D-Trp12,Tyr34]-bPTH(7-34) is highly sensitive to β-arrestin2 expression, suggesting that its actions are not merely reflective of PTH1R antagonism [71]. Applying geneset enrichment analysis to differentially expressed transcripts offers a means to probe the biological processes impacted by each ligand in vivo [72,73]. As shown in Fig. 3C, eight weeks treatment of wild type male mice C57BL/6 mice with hPTH(1-34) leads to predictable changes in pathways associated with embryologic skeletal patterning and PTH actions in bone, including Wnt/β-catenin signaling, BMP signaling, TGF-β signaling, PI3K/AKT signaling, and ERK/MAPK signaling, and processes associated with bone formation and turnover, mineralization and resorption, and skeletal patterning and development [76–78].
Informatic deconvolution of biased GPCR signaling mechanisms from in vivo pharmacological experimentation
2016, MethodsCitation Excerpt :Our previous research has proven that [D-Trp12,Tyr34]-bPTH(7-34) [bPTH(7-34)] demonstrates arrestin pathway-selective biased agonism of the parathyroid hormone type 1 receptor (PTH1R). Using easily controlled systems, e.g. within in vitro settings, bPTH [7–34] exhibits classical efficacy reversal compared to the endogenous ligand, acting as an inverse PTH1R agonist for Gαs coupling and an agonist for arrestin-dependent signaling, e.g. ERK1/2 signaling, cell migration and anti-apoptotic signaling [13–15]. In more complex, less well-controlled environments, i.e. in vivo, the intermittent injection of bPTH(7-34) increases multiple bone density/integrity indices without stimulating osteoclast proliferation and bone resorption that are induced in the same conditions by the endogenous agonist counterpart, hPTH(1-34) [14].
Exploring G protein-coupled receptor signaling networks using SILAC-based phosphoproteomics
2016, MethodsCitation Excerpt :Geneset enrichment analysis (GSEA) is a statistical approach that compares an experimentally determined list of regulated factors, e.g. phosphoproteins or mRNA transcripts, to a curated database of genes/proteins involved in specific signaling pathways/biological processes, to determine the probability of pathway regulation based on the overrepresentation of observed factors in the database pathway/process cluster. There are multiple freely available pathway databases and facile calculation programs to facilitate these analyses [81–83]. Because co-regulated geneset databases are themselves based on empiric data and not fully, or even correctly, annotated, such analyses should be considered exploratory in nature.
GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process
2023, International Journal of Molecular Sciences