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.

Public Health Relevance Statement Affecting approximately 50 million Americans, hypertension is the most prevalent chronic disease in the United States and a major contributor to mortality and vascular morbidity. Heart failure is also one of the main causes of mortality in the developed world. b1-adrenergic receptors are major regulators of these disease states; and therefore, understanding the molecular basis of b1-adrenergic receptor structure and function is directly related to the public health.