Zolk O, Kilter H, Flesch M, Mansier P, Swynghedauw B, Schnabel P, Böhm M
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Biochem Biophys Res Commun. 1998 Jul 30;248(3):801-5. doi: 10.1006/bbrc.1998.9030.
To assess functional and cellular effects of myocardial beta 1-adrenoceptor overexpression, alterations of the beta-adrenergic signal transduction pathway and contractile function in transgenic mice with atrial overexpression of the human beta 1-adrenoceptor were investigated. Radioligand binding experiments confirmed a 5- to 6-fold increase in beta-adrenoceptor density and a 2.7-fold increase in high-affinity binding sites in atria of transgenic mice. Dose-response curves for isoprenaline-induced force of contraction showed unchanged maximum effects but significantly increased pD2 values. Basal, MnCl2- and isoprenaline-stimulated adenylyl cyclase activities did not significantly differ, whereas the Gpp(NH)p and forskolin effect tends to be reduced in transgenic mice. The level of Gi alpha (pertussis toxin-catalyzed ADP-ribosylation) was unchanged, whereas the bioactivity of Gs alpha (reconstitution experiments into S49 cyc- cell membranes) was reduced by about 19% in the transgenic group. These results suggest that overexpressed beta 1-adrenoceptors act as functional spare receptors. In addition, increased beta 1-adrenoceptor density is associated with a decrease in Gs alpha-activity.
为评估心肌β1 -肾上腺素能受体过表达的功能和细胞效应，研究了人β1 -肾上腺素能受体在心房过表达的转基因小鼠中β -肾上腺素能信号转导通路的改变和收缩功能。放射性配体结合实验证实，转基因小鼠心房中β -肾上腺素能受体密度增加了5至6倍，高亲和力结合位点增加了2.7倍。异丙肾上腺素诱导的收缩力剂量反应曲线显示最大效应未改变，但pD2值显著增加。基础、MnCl2和异丙肾上腺素刺激的腺苷酸环化酶活性无显著差异，而转基因小鼠中Gpp(NH)p和福斯可林的效应趋于降低。Giα（百日咳毒素催化的ADP -核糖基化）水平未改变，而转基因组中Gsα（重构到S49 cyc -细胞膜中的实验）的生物活性降低了约19%。这些结果表明，过表达的β1 -肾上腺素能受体作为功能性备用受体起作用。此外，β1 -肾上腺素能受体密度增加与Gsα活性降低有关。
