Ivy leaves dry extract EA 575^® mediates biased β₂-adrenergic receptor signaling

Background β₂-adrenergic receptor (β₂-AR) stimulation activates the G protein/cAMP pathway, which is opposed by the GRK2/β-arrestin 2 pathway. The latter is of disadvantage in the treatment of respiratory diseases. EA 575^® is capable of mediating biased β₂-AR signaling.

Methods The impact of EA 575^® on β₂-adrenergic signaling was tested in a dynamic mass redistribution assay in HEK wild-type and in HEK β-arrestin knock-out cells. GloSensor™ and PathHunter^® assays were used to investigate cAMP formation and recruitment of β-arrestin 2. Additionally the influence of EA 575^® on the NFκB transcriptional activity was determined in both HEK wild-type as well as HEK β-arrestin knock-out cells.

Results EA 575^® inhibits the recruitment of β-arrestin 2 and thereby enhances G protein/cAMP signaling under β₂-stimulating conditions, as evidenced by a corresponding increase in cAMP formation. While β₂-AR-mediated inhibition of NFκB transcriptional activity is β-arrestin-dependent, EA 575^® leads to significant inhibition of NFκB transcriptional activity in β-arrestin knock-out cells and thus via a β-arrestin-independent signaling pathway.

Conclusion EA 575^® is the first active phytopharmaceutical ingredient for which biased β₂-adrenergic activation has been described. This shift towards G protein/cAMP signaling provides the molecular basis for the clinically proven efficacy of EA 575^® in the treatment of lower respiratory tract diseases. In this light, EA 575^® could potentially reduce β-arrestin-mediated adverse effects in new combinatorial therapeutic approaches.

Publikationsverlauf

Artikel online veröffentlicht:
13. Dezember 2021