Lab Website 

http://sites.duke.edu/rajagopallab/

Lab Members

Sudarshan Rajagopal, MD, PhD
Primary Investigator

Postdoctoral Associates
Zhiyuan Ma, PhD
Postdoctoral Associate
zhiyuan.ma@dm.duke.edu

Xinyu Xiong, PhD
Postdoctoral Associate
xinyu.xiong@dm.duke.edu

Graduate Student
Jeffrey Smith
MSTP Student
js.smith@dm.duke.ed

Technical Staff
Nour Nazo, BS
Research Technician
nour.nazo@dm.duke.edu

Undergraduates
Priya Alagesan
Duke University Undergraduate '18
priya.alagesan@duke.edu

Rachel Glenn
Duke University Undergraduate
rachel.glenn@duke.edu

Jaimee Gundry
Duke University Undergraduate
jaimee.gundry@duke.edu

Research Interests

G protein-coupled receptors (GPCRs) are the most common transmembrane receptors in the human genome (over 800 members) and are some of the most sucessful 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.

The major interest of the Rajagopal lab is in understanding the phenomenon of biased agonism, especially as it relates to cardiovascular disease. Specifically, we are interested in signaling by GPCRs in pulmonary arterial hypertension (PAH), a rare disease of the pulmonary vasculature that leads to heart failure and death, and of the mechanisms underlying biased agonism in the chemokine family. Towards this goal, we have developed approaches for: 1) Assaying signaling through multiple pathways downstream of a receptor, including G protein signaing, arrestin and GRK recruitment and other reporter assays; 2) Quantifying ligand bias using such data; 3) Assessing the physiologic impact of such signaling in rodent models of PAH and inflammation. Our goal is to understand the “rules” that underlie biased agonism, and exploit them to develop better drugs for cardiovascular disease.

Select Publications

Rajagopal S, Bassoni DL, Campbell JJ, Gerard NP, Gerard CG, Wehrman TS. (2013) Biased Agonism as a Mechanism for Differential Signaling. J Biol Chem. 288(49): 35039-48. [PMID: 24145037]

Rajagopal S, Rajagopal K, Lefkowitz RJ. (2010) Teaching Old Receptors New Tricks: Biasing Seven-Transmembrane Receptors. Nat. Rev. Drug Discov. 9:373-86. Review. [PMID: 20431569]

Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP, Gerard C, Lefkowitz RJ. (2010) b-arrestin- but not G-protein-mediated Signaling by the “Decoy” Receptor CXCR7. Proc. Natl. Acad. Sci. USA. 107: 628-32. [PMID: 20018651]