Physiological Functions of Biased Signaling at the Chemokine Receptor CXCR3

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2019

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Abstract

G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and one of the most common drug targets. It is now well-established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, G protein receptor kinases, and beta-arrestins. Certain ligands can preferentially activate certain signaling cascades while inhibiting others, a phenomenon referred to as biased signaling. While biased signaling is observed in many ex-vivo assays, the physiological relevance of biased signaling is not well established. Using the chemokine receptor CXCR3, a receptor that regulates T cell function, and its endogenous chemokines CXCL9, CXCL10, and CXCL11, I established that endogenous biased signaling exists at CXCR3. After identifying small molecule biased CXCR3 agonists using cell-based assays, I utilized human samples and mouse models of T cell movement and inflammation to determine that differential activation of either the G protein or beta-arrestin signaling pathways downstream of CXCR3 produces distinct functional differences. I identified that beta-arrestin regulated-Akt signaling appears critical for full efficacy chemotaxis. I conclude that biased signaling at CXCR3 produces distinct physiological responses.

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Smith, Jeffrey (2019). Physiological Functions of Biased Signaling at the Chemokine Receptor CXCR3. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/18643.

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