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Biased activation of β2-AR/Gi/GRK2 signal pathway attenuated β1-AR sustained activation induced by β1-adrenergic receptor autoantibody
Ist Teil von
Cell death discovery, 2021-11, Vol.7 (1), p.340-340, Article 340
Ort / Verlag
New York: Springer Nature B.V
Erscheinungsjahr
2021
Link zum Volltext
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
Abstract
Heart failure is the terminal stage of many cardiac diseases, in which β
1
-adrenoceptor (β
1
-AR) autoantibody (β
1
-AA) has a causative role. By continuously activating β
1
-AR, β
1
-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of β
1
-AR by β
1
-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. β
2
-adrenoceptor (β
2
-AR) is involved in the regulation of β
1
-AR signaling. This research aimed to clarify the mechanism of the β
1
-AA-induced sustained activation of β
1
-AR and explore the role of the β
2
-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca
2+
levels were examined to detect the activation of β
1
-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of β
1
-AR. ICI118551 was used to assess β
2
-AR/Gi function in β
1
-AR sustained activation induced by β
1
-AA in vitro and in vivo. Monoclonal β
1
-AA derived from a mouse hybridoma could continuously activate β
1
-AR. β
1
-AA-restricted β
1
-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein β-arrestin1/2, resulting in the cessation of β
1
-AR signaling. β
2
-AR could promote β
1
-AR endocytosis, as demonstrated by overexpressing/interfering with β
2
-AR in HL-1 cells, whereas β
1
-AA inhibited the binding of β
2
-AR to β
1
-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the β
2
-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of β
1
-AR by β
1
-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in β
1
-AA-positive mice. This study showed that β
1
-AA continuously activated β
1
-AR by inhibiting receptor endocytosis. Biased activation of the β
2
-AR/Gi/GRK2 signaling pathway could promote β
1
-AR endocytosis restricted by β
1
-AA, terminate signal transduction, and alleviate heart damage.