Analysis of functional selectivity through G protein-dependent and -independent signaling pathways at the adrenergic α2C receptor

Kurkó, Dalma; Kapui, Z.; Nagy, J; Lendvai, Balázs; Kolok, Sándor

doi:10.1016/j.brainresbull.2014.07.005

Cited by 12 publications

(8 citation statements)

References 122 publications

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“…We tested multiple α 2 ligands in this study. Although all these ligands promoted binding of both arrestin and spinophilin and gave similar results in our experimental readouts, it should be noted that these ligands likely exhibit different biases for the arrestin pathway, as described for the α 2C AR subtype previously [ 43 ]. Further investigation is needed to quantitatively compare the functional selectivity of these ligands to the α 2B AR, including arrestin and spinophilin recruitment.…”

Section: Discussionsupporting

confidence: 80%

Spinophilin Is Indispensable for the α2B Adrenergic Receptor-Elicited Hypertensive Response

Che

Chen

et al. 2015

PLoS ONE

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The α2 adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the α2A subtype elicits a hypotensive response whereas the α2B subtype mediates a hypertensive effect that counteracts the hypotensive response by the α2A subtype. We have previously shown that spinophilin attenuates the α2AAR-dependent hypotensive response; in spinophilin null mice, this response is highly potentiated. In this study, we demonstrate that spinophilin impedes arrestin-dependent phosphorylation and desensitization of the α2BAR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 α2BAR, a human variation that shows impaired phosphorylation and desensitization and is linked to hypertension in certain populations, exhibits preferential interaction with spinophilin over arrestin. Furthermore, Del301-303 α2BAR-induced ERK signaling is quickly desensitized in cells without spinophilin expression, showing a profile similar to that induced by the wild type receptor in these cells. Together, these data suggest a critical role of spinophilin in sustaining α2BAR signaling. Consistent with this notion, our in vivo study reveals that the α2BAR-elicited hypertensive response is diminished in spinophilin deficient mice. In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced. These data suggest that interaction with spinophilin is indispensable for the α2BAR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating α2AAR-mediated hypotensive response, suggesting that spinophilin regulation of these closely related receptor subtypes can result in distinct functional outcomes in vivo. Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.

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Section: Discussionsupporting

confidence: 80%

Spinophilin Is Indispensable for the α2B Adrenergic Receptor-Elicited Hypertensive Response

Che

Chen

et al. 2015

PLoS ONE

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“…Clonodine, moxonidine, and oxymetozaline showed a degree of bias toward β-Arrestin. 20 All four of these molecules contained scaffold when looking at E Max, it has 79% compared to 1 and 30 that have 62% and 73%. In retrospect, our scaffold has a higher bias for β-arr.…”

Section: Resultsmentioning

confidence: 99%

BiasNet: A model to predict ligand bias towards GPCR signaling

Sanchez¹,

KC²,

Franco³

et al. 2021

Preprint

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Signaling bias is a feature of many G–protein coupled receptor (GPCR) modulating drugs with clinical implications. Whether it is therapeutically advantageous for a drug to be G Protein biased or β-Arrestin (β-Arr) biased, depends on the context of the signaling pathway. Here, we explored GPCR ligands that exhibit biased signaling to gain insights into scaffolds and pharmacophores that leads to bias. More specifically, we used BiasDB, a database containing information about GPCR biased ligands and all ligands which show a (β-Arr) / G protein bias or a G protein / β-Arr bias are considered for the study. Four machine learning models were trained on these ligands to classify them. The features which were most important for training the models were analyzed. Two of these features (number of secondary amines and number of aromatic amines) were more prevalent in β-Arr biased ligands. After training a Random Forest model on HierS scaffolds, we found five scaffolds which demonstrated G protein or β-Arr bias. We also conducted t-SNE clustering, observing correspondence between unsupervised and supervised machine learning methods. To increase the applicability of our work, we developed a web implementation of our models which can predict bias based on a user-provided SMILES patterns. Our web implementation is available at: drugdiscovery.utep.edu/biasnet.

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“…We selected histamine receptors (HRs) [22,23] and sphingosine-1-phosphate receptors (S1PRs) [24] for which we used the respective endogenous ligands histamine and S1P. We also selected a2-adrenergic receptors (a2ARs) [25] and used UK 14304 (UK), also called brimonidine, a widely used full agonist with very high potency and selectivity [26]. To examine the activation of ERK by the three different GPCRs, we added a saturating concentration of agonist to the HeLa cell line expressing the KTR reporter.…”

Section: Activation Dynamics Of Erk After Gpcr Activationmentioning

confidence: 99%

Heterogeneity and dynamics of ERK and Akt activation by G protein-coupled receptors depend on the activated heterotrimeric G proteins

Chavez-Abiega

Grönloh

Gadella

et al. 2021

Preprint

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Kinases are fundamental regulators of cellular functions and play key roles in GPCR-mediated signaling pathways. Kinase activities are generally inferred from cell lysates, hiding the heterogeneity of the individual cellular responses to extracellular stimuli. Here, we study the dynamics and heterogeneity of ERK and Akt in genetically identical cells in response to activation of endogenously expressed GPCRs. We use kinase translocation reporters, high-content imaging, automated segmentation and clustering methods to assess cell-to-cell signaling heterogeneity. We observed ligand-concentration dependent response kinetics to histamine, α2-adrenergic, and S1P receptor stimulation that varied between cells. By using G protein inhibitors, we observed that Gq mediated the ERK and Akt responses to histamine. In contrast, Gi was necessary for ERK and Akt activation in response to α2-adrenergic receptor activation. ERK and Akt were also strongly activated by S1P, showing high heterogeneity at the single cell level, especially for ERK. In all cases, the cellular heterogeneity was not explained by distinct pre-stimulation levels or saturation of the measured response. Cluster analysis of time-series derived from 68,000 cells obtained under the different conditions revealed several distinct populations of cells that display similar response dynamics. The single-cell ERK responses to histamine and UK showed remarkably similar dynamics, despite the activation of different heterotrimeric G proteins. In contrast, the ERK response dynamics to S1P showed high heterogeneity, which was reduced by the inhibition of Gi. To conclude, we have set up an imaging and analysis strategy that reveals substantial cell-to-cell heterogeneity in kinase activity driven by GPCRs.

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Analysis of functional selectivity through G protein-dependent and -independent signaling pathways at the adrenergic α2C receptor

Cited by 12 publications

References 122 publications

Spinophilin Is Indispensable for the α2B Adrenergic Receptor-Elicited Hypertensive Response

Spinophilin Is Indispensable for the α2B Adrenergic Receptor-Elicited Hypertensive Response

BiasNet: A model to predict ligand bias towards GPCR signaling

Heterogeneity and dynamics of ERK and Akt activation by G protein-coupled receptors depend on the activated heterotrimeric G proteins

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