Department of Pharmacology, University of California, Davis, Davis, CADepartment of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana, Urbana, IL.
Department of Pharmacology, University of California, Davis, Davis, CA.
Diabetes. 2014 Aug;63(8):2676-89. doi: 10.2337/db13-1763. Epub 2014 Mar 27.
Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.
胰岛素和肾上腺素能刺激是两个不同的调节系统，在某些病理生理情况下可能相互作用。在这里，我们在心脏中表征了胰岛素受体（IR）和β2-肾上腺素能受体（β2AR）组成的复合物。在不同条件下，IR/β2AR 复合物会发生动态解离，例如用胰岛素进行 Langendorff 灌注心脏，或体内进行正常血糖高胰岛素钳夹。胰岛素激活 IR 会诱导β2AR 的蛋白激酶 A（PKA）和 G 蛋白受体激酶 2（GRK2）磷酸化，从而促进β2AR 与抑制性 G 蛋白 Gi 偶联。IR 诱导的β2AR 磷酸化依赖于 IRS1 和 IRS2。胰岛素预处理后，激活的β2AR-Gi 信号有效地减弱了β-肾上腺素刺激后心肌细胞中 cAMP/PKA 活性，从而抑制了肌浆网蛋白磷酸化和 Langendorff 灌注心脏中肌细胞的收缩反应。这些数据表明，高胰岛素血症状态下增加的 IR 信号可能直接损害βAR 调节的心肌收缩力。这种β2AR 依赖性的 IR 和βAR 信号串扰为这些信号级联在心脏和其他组织或器官中的广泛相互作用提供了分子基础，这可能有助于胰岛素抵抗状态下代谢和心血管功能障碍的病理生理学。
