Rao Tadimeti S, Lariosa-Willingham Karen D, Lin Fen-Fen, Palfreyman Emma L, Yu Naichen, Chun Jerold, Webb Michael
Merck Research Laboratories, 3535 General Atomics Court, Building 1, San Diego, CA 92121, USA.
Brain Res. 2003 Nov 14;990(1-2):182-94. doi: 10.1016/s0006-8993(03)03527-3.
Lysophosphatidic acid (1-acyl-2-lyso-sn-glycero-3-phosphate; LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids which respectively act as agonists for the G-protein-coupled lpA receptors (LPA1, LPA2, and LPA3) and s1p receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), collectively referred to as lysophospholipid receptors (lpR). Since astrocytes are responsive to LPA and S1P, we examined mechanisms of lpR signaling in rat cortical secondary astrocytes. Rat cortical astrocyte mRNA expression by quantitative TaqMan polymerase chain reaction (PCR) analysis revealed the following order of relative expression of lpR mRNAs: s1p3>s1p1>lpa1>s1p2=lpa3>>s1p5. Activation of lpRs by LPA or S1P led to multiple pharmacological effects, including the influx of calcium, phosphoinositide (PI) hydrolysis, phosphorylation of extracellular receptor regulated kinase (ERK) and release of [3H]-arachidonic acid (AA). These signalling events downstream of lpR activation were inhibited to varying degrees by pertussis toxin (PTX) pretreatment or by the inhibition of sphingosine kinase (SK), a rate-limiting enzyme in the biosynthesis of S1P from sphingosine. These results suggest that astrocyte lpR signalling mechanisms likely involve both Gi- and Gq-coupled GPCRs and that receptor-mediated activation of SK leads to intracellular generation of S1P, which in turn amplifies the lpR signalling in a paracrine/autocrine manner.
溶血磷脂酸（1-酰基-2-溶血-sn-甘油-3-磷酸；LPA）和1-磷酸鞘氨醇（S1P）是生物活性磷脂，它们分别作为G蛋白偶联的LPA受体（LPA1、LPA2和LPA3）和S1P受体（S1P1、S1P2、S1P3、S1P4和S1P5）的激动剂，这些受体统称为溶血磷脂受体（LpR）。由于星形胶质细胞对LPA和S1P有反应，我们研究了大鼠皮质继发性星形胶质细胞中LpR信号传导的机制。通过定量TaqMan聚合酶链反应（PCR）分析大鼠皮质星形胶质细胞mRNA表达，揭示了LpR mRNA相对表达的以下顺序：S1P3>S1P1>LPA1>S1P2 = LPA3>>S1P5。LPA或S1P激活LpR导致多种药理作用，包括钙内流、磷酸肌醇（PI）水解、细胞外受体调节激酶（ERK）磷酸化以及[3H]-花生四烯酸（AA）释放。百日咳毒素（PTX）预处理或抑制鞘氨醇激酶（SK）（鞘氨醇生物合成中从鞘氨醇生成S1P的限速酶）可不同程度地抑制LpR激活下游的这些信号事件。这些结果表明，星形胶质细胞LpR信号传导机制可能涉及Gi和Gq偶联的GPCR，并且受体介导的SK激活导致细胞内生成S1P，进而以旁分泌/自分泌方式放大LpR信号。
