Zeitschrift für Phytotherapie 2022; 43(S 01): S44
DOI: 10.1055/s-0042-1749283
Abstracts Poster | Phytotherapie 2022 – innovativ

Ivy leaves dry extract EA 575®​ enhances G protein/cAMP pathway and simultaneously inhibits GRK2/β-arrestin 2 pathway leading to a biased β2-adrenergic receptor signaling

F Meurer
1   Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Germany
,
J Schulte-Michels
1   Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Germany
,
H Häberlein
1   Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Germany
,
S Franken
1   Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Germany
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Introduction β2-Adrenergic receptor (β2-AR) stimulation activates the G protein/cAMP pathway, which is opposed by the GRK2/β-arrestin 2 pathway. The former leads to therapeutically desirable effects, whereas the latter results in internalisation of β2-AR, which decreases β2-adrenergic responsiveness in the airways and is disadvantageous in the treatment of respiratory diseases.

Aim The aim of the present study was to investigate whether the ivy leaves dry extract EA 575®​ is mediating biased β2-AR signaling.

Method PathHunter®​ and GloSensor™ assays were used to investigate recruitment of β-arrestin 2 and cAMP formation. Internalisation was determined with live-cell imaging and Nano-Glo®​ HiBiT Extracellular Detection System. β2-AR phosphorylation was investigated via in-cell Western.

Results α-Hederin identified in EA 575®​ indirectly inhibits GRK2-mediated phosphorylation of β2-AR [1], which is the reason for the decrease in recruitment of β-arrestin 2 by EA 575®​ [2]. This leads to an inhibition of β2-AR internalisation [3], which in turn results in an increased β2-adrenergic responsiveness, as evidenced by a corresponding increase in cAMP formation [2].

Conclusion EA 575®​ is the first phytopharmaceutical ingredient for which biased β2-adrenergic activation has been described. The shift towards G protein/cAMP signaling provides the molecular basis for the positive results of EA 575®​ as a cough medication with bronchospasmolytic and secretolytic activities in clinical use for acute bronchitis. Furthermore, a reduction of β-arrestin-mediated adverse effects by EA 575®​ in new combinatorial therapeutic approaches is possible.



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Artikel online veröffentlicht:
13. Juni 2022

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  • References

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  • 3 Sieben A. et al. Biochemistry 2009; 48: 3477–3482
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