Murao Naoya, Morikawa Risa, Seino Yusuke, Shimomura Kenju, Maejima Yuko, Yamada Yuichiro, Suzuki Atsushi
Department of Endocrinology, School of Medicine, Diabetes and Metabolism, Fujita Health University, Toyoake, Japan.
Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto, Japan.
Pharmacol Res Perspect. 2025 Apr;13(2):e70092. doi: 10.1002/prp2.70092.
β-adrenergic blockers (β-blockers) are extensively used to inhibit β-adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β-blockers on mouse pancreatic β-cells. Unexpectedly, high concentrations (100 μM) of β-blockers (propranolol and bisoprolol) paradoxically increased cAMP levels 5-10 fold, enhanced Ca influx, and stimulated a 2-4 fold increase in glucose- and glimepiride-induced insulin secretion in MIN6-K8 clonal β-cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β-adrenoceptors in these cells. Mechanistically, the cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca-induced Ca release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca influx via voltage-dependent Ca channels. These effects contradict the conventional understanding of the pharmacology of β-blockers, highlighting the variability in β-blocker actions depending on the experimental context.
β-肾上腺素能阻滞剂（β-阻滞剂）被广泛用于抑制多种细胞类型中的β-肾上腺素受体激活及随后的环磷酸腺苷（cAMP）生成。在本研究中，我们对β-阻滞剂对小鼠胰腺β细胞的作用进行了表征。出乎意料的是，高浓度（100μM）的β-阻滞剂（普萘洛尔和比索洛尔）反常地使cAMP水平升高了5至10倍，增强了钙内流，并刺激MIN6-K8克隆β细胞和分离的小鼠胰岛中葡萄糖和格列美脲诱导的胰岛素分泌增加了2至4倍。尽管这些细胞中β-肾上腺素受体的表达极少，但仍观察到了这些效应。从机制上讲，cAMP的增加通过蛋白激酶A（PKA）导致兰尼碱受体2（RYR2）磷酸化，触发钙诱导的钙释放（CICR）。CICR随后激活瞬时受体电位阳离子通道亚家族M成员5（TRPM5），导致通过电压依赖性钙通道的钙内流增加。这些效应与对β-阻滞剂药理学的传统理解相矛盾，突出了β-阻滞剂作用因实验背景而异的变异性。
