Editors' ChoiceGPCR SIGNALING

New connections: Taking advantage of bias

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Sci. Signal.  06 Nov 2018:
Vol. 11, Issue 555, eaav9344
DOI: 10.1126/scisignal.aav9344

Biased chemokine receptor agonists and antagonists that target specific signaling pathways may provide therapeutic benefit.

G protein–coupled receptors (GPCRs) can exhibit so-called biased agonism, such that distinct ligands activate either a G protein–dependent pathway or a β-arrestin–dependent pathway. The type of pathway activated has important implications. For example, mu opioid receptor ligands that activate G proteins mediate pain relief, whereas those that activate β-arrestins cause side effects, such as depressed breathing and dependence. Thus, there is much interest in developing therapies that specifically target one pathway depending on the desired outcome. Chemokine receptors are a subfamily of GPCRs and their peptide ligands, called chemokines, attract immune cells to sites of infection and inflammation. In this issue of Science Signaling, Smith et al. investigated biased signaling mediated by the chemokine receptor CXCR3. The authors used small-molecule receptor agonists and found that topical application of a β-arrestin–biased, but not a G protein–biased, agonist worsened inflammation in a mouse model of contact hypersensitivity. The β-arrestin–biased agonist stimulated T cell migration and activated the kinase Akt to a greater extent than did the G protein–biased agonist, which led to enhanced recruitment of cells to inflammatory sites.

In studying signaling by the chemokine receptor and HIV-1 co-receptor CCR5 in response to two endogenous ligands, RANTES and MIP-1α, and several RANTES analogs, Lorenzen et al., as reported in the Science Signaling Archives, found evidence of another type of signaling bias. CCR5 can inhibit generation of the second messenger cAMP by stimulating Gi/o family G proteins, whereas it induces Ca2+ signaling through Gq/11 family G proteins, which causes inflammation. An ideal therapeutic would stimulate CCR5 internalization to prevent HIV-1 from binding to it but would also prevent inflammatory signaling. The authors found that the RANTES analogs differentially activated the two different G protein types and that those compounds that preferentially activated CCR5 to signal through Gi/o might block HIV-1 infection without inducing inflammation.

The CXCR4 antagonist AMD3100 prevents the accumulation of leukemic cells in the bone marrow, thereby increasing the efficacy of chemotherapies. However, cells can become tolerant to AMD3100, which then enables CXCR4 accumulation on the cell surface, causing the cells to be retained in the bone marrow where they are less accessible to chemotherapy. In the Science Signaling Archives, Hitchinson et al. showed that a peptide derived from CXCR4 stopped tolerance from occurring by acting as a biased antagonist of G protein signaling but not β-arrestin–mediated receptor internalization. Further experiments showed that a nonpeptide, small-molecule inhibitor also prevented tolerance from developing, suggesting that biased GPCR antagonists could be used as therapies for patients that develop tolerance to nonbiased antagonists. Together, these studies indicate that the selective use of biased agonists or antagonists could fine-tune chemokine receptor signaling to control distinct physiological responses and provide therapeutic benefit.

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