Biased agonism at chemokine receptors.


In the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies, leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specific cellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacy and safer side effect profiles.





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Publication Info

Eiger, Dylan Scott, Noelia Boldizsar, Christopher Cole Honeycutt, Julia Gardner and Sudarshan Rajagopal (2021). Biased agonism at chemokine receptors. Cellular signalling, 78. p. 109862. 10.1016/j.cellsig.2020.109862 Retrieved from

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Sudarshan Rajagopal

Associate Professor of Medicine

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 resesarch 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.

Much of our research focuses on the chemokine system, which consists of approximately twenty receptors and fifty ligands that display considerable promiscuity with each other in the regulation of immune cell function in inflammatory diseases. Research from our group and others have shown that many of these ligands act as biased agonists when signaling through the same receptor. We use models of inflammation such as contact hypersensitivity and pulmonary arterial hypertension (PAH). PAH is a disease of the pulmonary arterioles that results in right heart failure and most of its treatments target signaling by GPCRs. We use multiple approaches to probe these signaling mechanisms, including in-house pharmacological assays, advanced phosphoproteomics and single cell RNA sequencing.

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