SignificanceModeling immune responses in vitro is critical for studying many facets of the B cell response. We show that during culture without stimulation, mouse B cells undergo massive changes in gene expression. Many of these changes are promoted by GPR174 signaling via Gαs. GPR174 and Gαs also contribute to reduced B cell viability during culture. We suggest that GPR174 antagonists may be useful to reduce the shift in gene expression and to augment B cell survival during culture. We also provide evidence that ligand engagement of GPR174 can activate this pathway in vivo. Variants in the GPR174 locus have been associated with autoimmune diseases. Our findings provide knowledge for understanding how alterations in GPR174 expression may contribute to disease.

2021-07-22·Journal of Medicinal Chemistry1区 · 医学

Switching Lysophosphatidylserine G Protein-Coupled Receptor Agonists to Antagonists by Acylation of the Hydrophilic Serine Amine

1区 · 医学

Article

作者: Inoue, Asuka ; Aoki, Junken ; Ohwada, Tomohiko ; Uwamizu, Akiharu ; Yan, Ge ; Sayama, Misa ; Chen, Luying ; Otani, Yuko ; Ikubo, Masaya

Three human G protein-coupled receptors (GPCRs)-GPR34/LPS₁, P2Y10/LPS₂, and GPR174/LPS₃-are activated specifically by lysophosphatidylserine (LysoPS), an endogenous hydrolysis product of a cell membrane component, phosphatidylserine (PS). LysoPS consists of l-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages. We previously generated potent and selective GPCR agonists by modification of the three modules and the ester linkage. Here, we show that a novel modification of the hydrophilic serine moiety, that is, N-acylations of the serine amine, converted a GPR174 agonist to potent GPR174 antagonists. Structural exploration of the amide functionality provided access to a range of activities from agonist to partial agonist to antagonist. The present study would provide a new strategy for the development of lysophospholipid receptor antagonists.

2015-06-29·Journal of Experimental Medicine1区 · 医学

The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function

1区 · 医学

Article

作者: Cyster, Jason G. ; Xu, Ying ; Barnes, Michael J. ; An, Jinping ; Huang, Yong ; Li, Chien-Ming

Regulatory T cell (T reg cell) numbers and activities are tightly calibrated to maintain immune homeostasis, but the mechanisms involved are incompletely defined. Here, we report that the lysophosphatidylserine (LysoPS) receptor GPR174 is abundantly expressed in developing and mature T reg cells. In mice that lacked this X-linked gene, T reg cell generation in the thymus was intrinsically favored, and a higher fraction of peripheral T reg cells expressed CD103. LysoPS could act in vitro via GPR174 to suppress T cell proliferation and T reg cell generation. In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon. Gpr174−/Y mice were less susceptible to experimental autoimmune encephalomyelitis than wild-type mice, and GPR174 deficiency in T reg cells contributed to this phenotype. This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174. As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.

100 项与 GPR174 inhibitor (Omeros) 相关的药物交易

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