Potential role of G protein-coupled receptor 3 in mast cells following brain ischemia

[Speaker] Shigeru Tanaka:1
[Co-author] Yuhki Yanase:2, Masahiro Yamamoto:1, Tatsuhiro Miyagi:1, Hiroko Shiraki:1, Izumi Hide:1, Norio Sakai:1
1:Department of Molecular and Pharmacological Neuroscience, Hiroshima University Graduate School of Biomedical & Health Sciences, Japan, 2:Department of Dermatology, Hiroshima University Graduate School of Biomedical & Health Sciences, Japan

G protein-coupled receptor 3 (GPR3) is a member of the class A rhodopsin-type GPCR family and is highly expressed in various neurons. GPR3 is unique in its ability to constitutively activate the Gαs protein without the addition of ligands, which elevates the basal level of intracellular cAMP. We have previously reported that the neuronal expression of GPR3 enhances neurite outgrowth (Tanaka et al., JBC 2007), modulates the proliferation of cerebellar granule cell precursors (Tanaka et al., PLoS One 2009), and is associated with neuronal survival (Tanaka et al., Neurobiol Dis 2014). However, the physiological functions of GPR3 following brain ischemia have not been elucidated. Here, we investigated whether GPR3 expression is modulated following brain ischemia. GPR3 mRNA expression was transiently upregulated in the ischemic hemisphere as early as 4 h after transient middle cerebral artery occlusion in Wistar rats and C57BL/6 mice. Surprisingly, GPR3 promoter activity was decreased in neurons in the ischemic hemisphere in mice. These results prompted us to identify the "GPR3 upregulating cells" following brain ischemia. Analyses of Percoll density gradients from the ischemic brain homogenate revealed abundant GPR3 expression in the mast cell-rich fraction. We further investigated GPR3 expression using bone marrow-derived mast cells (BMMCs). In the unstimulated condition, GPR3 mRNA expression was scarcely detectable but was highly upregulated as early as 1 to 2 h after BMMC stimulation. The induction of GPR3 tended to negatively modulate degranulation in BMMCs. These results suggested a potential role of GPR3 in modulating mast cell degranulation, thereby affecting the pathophysiology of brain ischemia.
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