Altered Immune Response in Mice Deficient for the G Protein-coupled Receptor GPR34

Abstract

The X-chromosomal GPR34 gene encodes an orphan G i protein-coupled receptor that is highly conserved among vertebrates. To evaluate the physiological relevance of GPR34, we generated a GPR34-deficient mouse line. GPR34-deficient mice were vital, reproduced normally, and showed no gross abnormalities in anatomical, histological, laboratory chemistry, or behavioral investigations under standard housing. Because GPR34 is highly expressed in mononuclear cells of the immune system, mice were specifically tested for altered functions of these cell types. Following immunization with methylated BSA, the number of granulocytes and macrophages in spleens was significantly lower in GPR34-deficient mice as in wild-type mice. GPR34-deficient mice showed significantly increased paw swelling in the delayed type hypersensitivity test and higher pathogen burden in extrapulmonary tissues after pulmonary infection with Cryptococcus neoformans compared with wild-type mice. The findings in delayed type hypersensitivity and infection tests were accompanied by significantly different basal and stimulated TNF-␣, GM-CSF, and IFN-␥ levels in GPR34-deficient animals. Our data point toward a functional role of GPR34 in the cellular response to immunological challenges. G protein-coupled receptors (GPCR)2 form the largest gene family among transmembrane receptors, including more than 900 genes in humans and other mammals (1). A great number of stimuli, such as light, hormones, neurotransmitters, peptides, and nucleotides, activate the distinct receptors. Nonodorant receptors form about one-third of the GPCR repertoire. Although more than 200 non-odorant GPCR have been assigned to specific agonists and functions, about 155 socalled "orphan" GPCR (2) await identification of their physiological relevance. The importance of GPCR in controlling almost every physiological function makes this receptor family the most frequently used target for therapeutic drugs. Therefore, unveiling the function of orphan GPCR is a central issue in academic and industrial research.Among the five structurally different GPCR families (1, 3), the rhodopsin-like receptors form the largest in humans and other vertebrates. The rhodopsin-like family is divided further into subfamilies and groups. The P2Y 12 -like receptor group includes the ADP receptors P2Y 12 and P2Y 13 , the UDP-glucose receptor P2Y 14 , and the orphan receptors GPR87, GPR82, and GPR34 (4). Apart from the ADP receptor P2Y 12 , which has a central role in platelet aggregation and is the therapeutic target of clopidogrel (5, 6), very little is known about the function of the other members of this group.GPR34, an orphan receptor of the P2Y 12 -like receptor group, was first discovered by mining GenBank TM for novel GPCR sequences and homology cloning and has been assigned to the human X chromosome (7,8). Phylogenetic studies revealed that GPR34 has been highly conserved over the past 450 million years of vertebrate evolution, and no GPR34-deficient vertebrate has been identified yet (9). To date, there i...

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“…Only nine genes were differentially expressed in the cortex of mutant KI mice; Camkk1, Cort, Ctxn3, Gli3, Gpr23, Gpr34, Lsm10, Tnnc1, and Tom1l2. Differential expression of cortical Camkk1, Gpr34, Tom1l2, and Cort gives an indication for an immune-related component, as these genes seem involved in the immune response (17)(18)(19)(20)(21).…”

Novel lysophosphoplipid receptors: their structure and function

“…However, as stated above, LPT, a potent inducer of mast cell degranulation, did not activate GPR34 ( 22 ). In addition, peritoneal mast cells from GPR34-defi cient mice still responded to LysoPS ( 41 ). Thus, it is likely that GPR34 is not involved in the mast cell degranulation response induced by LysoPS.…”

“…Because GPR34 is highly expressed in mononuclear cells of the immune system, LysoPS appears to serve as an immunomodulator through GPR34 in response to immunological challenges. Further studies are needed to elucidate the Liebscher et al ( 41 ) demonstrated that GPR34 from carp, a kind of fi sh, did react strongly with LysoPS . On the other hand, the result of the initial study by Sugo et al ( 35 ) was confi rmed by Kitamura et al ( 42 ), in which activation of GPR34 was evaluated by a Ca 2+ mobilization assay and by a newly developed transforming growth factor (TGF) ␣ shedding assay.…”

“…There is some controversy over whether LysoPS is a real ligand for mammalian GPR34 ( 41 ). On the one hand, Recently, Bratton and colleagues showed that LysoPS was generated in neutrophils by an oxidation-dependent mechanism and served as an endogenous anti-infl ammatory mediator by stimulating the clearance of recruited neutrophils by macrophages, contributing to the resolution of infl ammation (30)(31)(32).…”

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