The effect of Gi‐protein inactivation on basal, and β1‐ and β2AR‐stimulated contraction of myocytes from transgenic mice overexpressing the β2‐adrenoceptor

The atria and ventricles of transgenic mice (TGβ2) with cardiac overexpression of the human β2‐adrenoceptor (β2AR) were initially reported to show maximum contractility in the absence of β‐AR stimulation. However, we have previously observed a different phenotype in these mice, with myocytes showing...

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Bibliographic Details
Published in:British journal of pharmacology 2000-10, Vol.131 (3), p.594-600
Main Authors: Gong, Haibin, Adamson, Dawn L, Ranu, Hardeep K, Koch, Walter J, Heubach, Jürgen F, Ravens, Ursula, Zolk, Oliver, Harding, Sian E
Format: Article
Language:English
Subjects:
Biological and medical sciences
Catecholaminergic system
Fundamental and applied biological sciences. Psychology
Heart
inhibitory G‐protein
Medical sciences
myocyte shortening
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
transgenic mice
Vertebrates: cardiovascular system
β2‐adrenoceptor overexpression
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Summary:The atria and ventricles of transgenic mice (TGβ2) with cardiac overexpression of the human β2‐adrenoceptor (β2AR) were initially reported to show maximum contractility in the absence of β‐AR stimulation. However, we have previously observed a different phenotype in these mice, with myocytes showing normal contractility but reduced βAR responses. We have investigated the roles of cyclic AMP and Gi in basal and βAR function in these myocytes. ICI 118,551 at inverse agonist concentrations decreased contraction by 32%. However, the cyclic AMP antagonist Rp‐cAMPS had no effect on contraction in TGβ2 myocytes, indicating that there was no tonic influence of raised cyclic AMP. These findings cannot be explained by the proposed model for inverse agonism, where the activated receptor (R*) raises cyclic AMP levels and so increases contraction in the absence of agonist. After pertussis toxin (PTX) pretreatment to produce inactivation of Gi, the basal contraction in 1 mM Ca2+ was increased in TGβ2 mice (7.82±0.47%, n=23) compared to LM mice (3.60±0.59%, n=11) (P
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0703591