Molecular Basis of B1-Adrenergic Receptor Function

项目说明 这项研究项目的长期目标是了解 B1-肾上腺素能受体激活异源三聚体G蛋白。高血压(高 高血压)和心脏病是全球性的健康问题。高血压可导致 严重的并发症，增加中风和死亡的风险。激活心脏b1- 肾上腺素能受体导致心率和收缩能力增加，从而促进心脏 输出。机制上，在b1肾上腺素能受体的刺激下，激活G-受体。 Gs蛋白可以刺激腺酰环化酶的活性。在本应用程序中，我们将重点介绍 基于b1肾上腺素能受体激活Gs蛋白的结构基础。我们将使用 生物物理、细胞和药理学方法以更深入地了解 这个激活过程。我们将研究G-蛋白的构象变化 在被b1肾上腺素能受体激活的过程中。我们将研究这种耦合 β_1肾上腺素能受体与不同G蛋白家族的特异性。这些研究 将促进我们对b1-肾上腺素能受体结构和功能的理解， 并有助于新一代b1肾上腺素能特异性抑制剂的未来开发 受体具有偏向的信号和较少的副作用。

Project Description The long-term objective of this research project is to understand the molecular basis of the activation of heterotrimeric G-proteins by b1-adrenergic receptor. Hypertension (high blood pressure) and heart disease are global health concerns. Hypertension can lead to severe complications and increase the risk of stroke and death. Activation of cardiac b1- adrenergic receptor leads to increased heart rate and contractility, thus boosting cardiac output. Mechanistically, following the stimulation of b1-adrenergic receptor, activated G- protein Gs leads to the stimulation of adenylyl cyclase. In this application, we will focus on the structural basis of activation of Gs-protein by b1-adrenergic receptors. We will use biophysical, cellular and pharmacological approaches to gain a deeper understanding of this activation process. We will investigate the conformational changes of G-proteins during their activation by b1-adrenergic receptors. We will examine the coupling specificity of b1-adrenergic receptors and different families of G-proteins. These studies will advance our understanding of the structure and function of b1-adrenergic receptors, and aid future development of new-generations of specific inhibitors of b1-adrenergic receptors with biased signaling and fewer side effects.