Beta-Arrestins and Receptor Signaling in the Vascular Endothelium.
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2020-12-23
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Abstract
The vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine kinases. The β-arrestins, multifunctional adapter proteins, have the potential to regulate all of these receptor families, although it is unclear as to whether they serve to integrate signaling across all of these different axes. Notably, the β-arrestins have been shown to regulate signaling by a number of receptors important in endothelial function, such as chemokine receptors and receptors for vasoactive substances such as angiotensin II, endothelin-1 and prostaglandins. β-arrestin-mediated signaling pathways have been shown to play central roles in pathways that control vasodilation, cell proliferation, migration, and immune function. At this time, the physiological impact of this signaling has not been studied in detail, but a deeper understanding of it could lead to the development of novel therapies for the treatment of vascular disease.
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Lee, Claudia, Gayathri Viswanathan, Issac Choi, Chanpreet Jassal, Taylor Kohlmann and Sudarshan Rajagopal (2020). Beta-Arrestins and Receptor Signaling in the Vascular Endothelium. Biomolecules, 11(1). pp. 1–17. 10.3390/biom11010009 Retrieved from https://hdl.handle.net/10161/22282.
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Sudarshan Rajagopal
I am a physician-scientist with a research focus on G protein-coupled receptor signaling in inflammation and vascular disease and a clinical focus on pulmonary vascular disease, as I serve as Co-Director of the Duke Pulmonary Vascular Disease Center. My research spans the spectrum from clinical research in pulmonary vascular disease, to translational research in cardiovascular disease, to the basic science of receptor signaling.
Our basic science research focuses on understanding and untapping the signaling potential of G protein-coupled receptors (GPCRs) to regulate inflammation in vascular disease. GPCRs are the most common transmembrane receptors in the human genome (over 800 members) and are some of the most successful targets for drug therapies. While it has been known for some time that these receptors signal through multiple downstream effectors (such as heterotrimeric G proteins and multifunctional beta arrestin adapter proteins), over the past decade it has been better appreciated that these receptors are capable of signaling with different efficacies to these effectors, a phenomenon referred to as “biased agonism”. Ligands can be biased, by activating different pathways from one another, and receptors can be biased, by signaling to a limited number of pathways that are normally available to them. Moreover, this phenomenon also appears to be common to other transmembrane and nuclear receptors. While a growing number of biased agonists acting at multiple receptors have been identified, there is still little known regarding the mechanisms underlying biased signaling and its physiologic impact. We use multiple approaches to probe these signaling mechanisms, including in-house pharmacological assays, advanced phosphoproteomics and single cell RNA sequencing.
Our translational research is focused on studying signaling in different forms of pulmonary hypertension (PH), a disease of the pulmonary vasculature that results in right heart failure. We have identified novel molecular mechanisms that contribute to the development of pulmonary arterial hypertension (PAH), a disease of the pulmonary arterioles. We have also used single cell RNA sequencing to identify the cell types and signaling pathways that contribute to chronic thromboembolic pulmonary hypertension (CTEPH).
Lastly, our clinical research program focuses on the application of novel imaging technologies for diagnosis, prognosis and management of PH. Most notably, this includes the application of hyperpolarized Xenon MRI, in collaboration with Dr. Bastiaan Driehuys in the Department of Radiology, to characterizing the physiological basis of gas exchange and hemodynamic abnormalities across all forms of PH. In collaboration with Dr. Fawaz Alenezi, we have applied advanced echo approaches for the management of PH.
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