Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

Junke Liu, Hengmin Tang, Chanjuan Xu, Shengnan Zhou, Xunying Zhu, Yuanyuan Li, Laurent Prézeau, Tao Xu, Jean-Philippe Pin (), Philippe Rondard (), Wei Ji () and Jianfeng Liu ()
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Junke Liu: Huazhong University of Science and Technology
Hengmin Tang: Huazhong University of Science and Technology
Chanjuan Xu: Huazhong University of Science and Technology
Shengnan Zhou: Huazhong University of Science and Technology
Xunying Zhu: Huazhong University of Science and Technology
Yuanyuan Li: Chinese Academy of Sciences
Laurent Prézeau: Université de Montpellier, CNRS, INSERM
Tao Xu: Chinese Academy of Sciences
Jean-Philippe Pin: Université de Montpellier, CNRS, INSERM
Philippe Rondard: Université de Montpellier, CNRS, INSERM
Wei Ji: Chinese Academy of Sciences
Jianfeng Liu: Huazhong University of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract G protein-coupled receptors (GPCRs) are important drug targets that mediate various signaling pathways by activating G proteins and engaging β-arrestin proteins. Despite its importance for the development of therapeutics with fewer side effects, the underlying mechanism that controls the balance between these signaling modes of GPCRs remains largely unclear. Here, we show that assembly into dimers and oligomers can largely influence the signaling mode of the platelet-activating factor receptor (PAFR). Single-particle analysis results show that PAFR can form oligomers at low densities through two possible dimer interfaces. Stabilization of PAFR oligomers through cross-linking increases G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. Reciprocally, β-arrestin prevents PAFR oligomerization. Our results highlight a mechanism involved in the control of receptor signaling, and thereby provide important insights into the relationship between GPCR oligomerization and downstream signaling.

Date: 2022
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DOI: 10.1038/s41467-022-34056-4

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