Identification of T Cell Death-associated Gene 8 (TDAG8) as a Novel Acid Sensing G-protein-coupled Receptor

Abstract

T cell death-associated gene 8 (TDAG8) is a G-proteincoupled receptor mainly expressed in lymphoid organs and cancer tissues. TDAG8 shares high amino acid sequence homologies with recently reported proton-sensing G-protein-coupled receptors, G2A, OGR1, and GPR4. Here we have identified TDAG8 as a novel proton-sensing receptor. Upon acid stimulation, stably expressed TDAG8 was internalized from the plasma membrane. As a signaling pathway downstream of TDAG8, accumulation of cyclic AMP was observed in response to solutions with a pH value lower than 7.2. Furthermore, RhoA activation and actin rearrangement were elicited by acidstimulated TDAG8. These results suggest that TDAG8 may play biological roles in immune response and cellular transformation under conditions accompanying tissue acidosis.

Secretory Phospholipases A2 Induce Neurite Outgrowth in PC12 Cells through Lysophosphatidylcholine Generation and Activation of G2A Receptor

“…Interestingly, activation of G2A at low pH was antagonized by LPC. Furthermore, structurally similar GPCR, TDAG8, has also been reported to respond to acidic pH (26,27). Wang et al reported that the pH response of TDAG8 was antagonized by its ligand, psychosine, which also attenuated the activation of OGR1 and GPR4 at low pH.…”

“…Furthermore, they described that SPC and LPC do not exert any effects on the generation of second messengers. Subsequently, pH-dependent activation of G2A (25) and TDAG8 (26,27) was reported; Mu-rakami et al (25) showed that previously proposed ligand of G2A, LPC, inhibited pH-dependent accumulation of inositol phosphate in cells expressing G2A, whereas Wang et al (26) described that cAMP generation in TDAG8-expressing cells was inhibited by psychosine. The latter authors also demonstrated that psychosine acts antagonistically to the pH-dependent generation of second messengers in GPR4-or OGR1-expressing cells.…”

Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages

“…For example, stimulation of OGR1 results in the activation of phospholipase C/Ca 2ϩ mobilization (12,13,18), and the stimulation of TDAG8 and GPR4 causes the activation of adenylyl cyclase/AMP accumulation (12,(15)(16)(17)(18). We therefore examined which OGR1 family receptors are expressed in mouse macrophages.…”

“…However, the signaling mechanism remains unknown. TDAG8 has been shown to be coupled to multisignaling pathways, including the G s protein/cAMP pathway and the G 12/13 protein/ pathway (15,16,18). To examine whether cAMP accumulation occurs by acidification in macrophages, we tried to measure the cellular cAMP content under the same experimental condition as that for cytokine production.…”

“…For example, extracellular acidification causes Ca 2ϩ mobilization in association with phospholipase C activation through OGR1 (12,13), activation of the Rho signaling pathway through G2A (14), and cAMP accumulation in association with adenylyl cyclase activation and activation of the Rho signaling pathway through TDAG8 (15)(16)(17) and GPR4 (12,18). These early signaling events have the potential to regulate the signaling pathways, leading to the production of proinflammatory cytokines (19).…”