TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor
TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor
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DOI：
10.1074/jbc.m406966200
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发表时间：
2004-10-29
影响因子：
4.8
通讯作者：
Okajima, F
中科院分区：
文献类型：
--
作者：
Wang, JQ;Kon, J;Okajima, F
据报道，T细胞死亡相关基因8（TDAG 8）是精神病的受体。然而，卵巢癌G蛋白偶联受体1（OGR 1）和GPR 4，与TDAG 8密切相关的G蛋白偶联受体（GPCR），最近被鉴定为分别刺激磷酸肌醇和cAMP产生的质子敏感或细胞外pH响应性GPCR。在本研究中，我们研究了TDAG 8是否感知细胞外pH值的变化。在用TDAG 8 cDNA转染的几种细胞类型中，cAMP响应于中性至酸性的细胞外pH而显著积累，在约pH 7.0-6.5处具有峰值响应。pH效应被铜离子抑制，并且在表达突变的TDAG 8的细胞中减少或丧失，其中组氨酸残基被改变为苯丙氨酸。在从TDAG 8-转染细胞制备的膜组分中，鸟苷5 '-O-（3-硫代三磷酸）结合活性和腺苷酸环化酶活性显着刺激响应中性和酸性pH值。细胞外质子对cAMP积累的浓度依赖性效应在精神病的存在下向右移动。在OGR 1和GPR 4表达细胞中也观察到pH依赖性作用的抑制性精神碱效应，但在天然和1-磷酸鞘氨醇受体表达细胞中，在任何pH下均未观察到前列腺素E-2和1-磷酸鞘氨醇诱导的作用。葡萄糖鞘氨醇和鞘氨醇磷酸胆碱同样抑制pH值依赖的行动，虽然在较小程度上。在小鼠胸腺细胞中也观察到了对Psychosine敏感和pH依赖的cAMP积累。我们的结论是，TDAG 8是一个质子敏感GPCR耦合腺苷酸环化酶和psychosine，其相关的lysosphingolipids的行为，如果他们对蛋白质敏感受体，包括TDAG 8，GPR 4，和OGR 1拮抗剂。
T cell death-associated gene 8 (TDAG8) has been reported to be a receptor for psychosine. Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4, G-protein-coupled receptors (GPCRs) closely related to TDAG8, however, have recently been identified as proton-sensing or extracellular pH-responsive GPCRs that stimulate inositol phosphate and cAMP production, respectively. In the present study, we examined whether TDAG8 senses extracellular pH change. In the several cell types that were transfected with TDAG8 cDNA, cAMP was markedly accumulated in response to neutral to acidic extracellular pH, with a peak response at approximately pH 7.0-6.5. The pH effect was inhibited by copper ions and was reduced or lost in cells expressing mutated TDAG8 in which histidine residues were changed to phenylalanine. In the membrane fractions prepared from TDAG8-transfected cells, guanosine 5'-O-(3-thiotriphosphate) binding activity and adenylyl cyclase activity were remarkably stimulated in response to neutral and acidic pH. The concentration-dependent effect of extracellular protons on cAMP accumulation was shifted to the right in the presence of psychosine. The inhibitory psychosine effect was also observed for pH-dependent actions in OGR1- and GPR4-expressing cells but not for prostaglandin E-2- and sphingosine 1-phosphate-induced actions in any pH in native and sphingosine 1-phosphate receptor-expressing cells. Glucosylsphingosine and sphingosylphosphorylcholine similarly inhibited the pH-dependent action, although to a lesser extent. Psychosine-sensitive and pH-dependent cAMP accumulation was also observed in mouse thymocytes. We concluded that TDAG8 is one of the proton-sensing GPCRs coupling to adenylyl cyclase and psychosine, and its related lysosphingolipids behave as if they were antagonists against protein-sensing receptors, including TDAG8, GPR4, and OGR1.