Hossain Md Shamim, Mineno Kurumi, Katafuchi Toshihiko
Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
PLoS One. 2016 Mar 2;11(3):e0150846. doi: 10.1371/journal.pone.0150846. eCollection 2016.
The special glycerophospholipids plasmalogens (Pls) are enriched in the brain and reported to prevent neuronal cell death by enhancing phosphorylation of Akt and ERK signaling in neuronal cells. Though the activation of Akt and ERK was found to be necessary for the neuronal cells survival, it was not known how Pls enhanced cellular signaling. To answer this question, we searched for neuronal specific orphan GPCR (G-protein coupled receptor) proteins, since these proteins were believed to play a role in cellular signal transduction through the lipid rafts, where both Pls and some GPCRs were found to be enriched. In the present study, pan GPCR inhibitor significantly reduced Pls-induced ERK signaling in neuronal cells, suggesting that Pls could activate GPCRs to induce signaling. We then checked mRNA expression of 19 orphan GPCRs and 10 of them were found to be highly expressed in neuronal cells. The knockdown of these 10 neuronal specific GPCRs by short hairpin (sh)-RNA lentiviral particles revealed that the Pls-mediated phosphorylation of ERK was inhibited in GPR1, GPR19, GPR21, GPR27 and GPR61 knockdown cells. We further found that the overexpression of these GPCRs enhanced Pls-mediated phosphorylation of ERK and Akt in cells. Most interestingly, the GPCRs-mediated cellular signaling was reduced significantly when the endogenous Pls were reduced. Our cumulative data, for the first time, suggest a possible mechanism for Pls-induced cellular signaling in the nervous system.
特殊的甘油磷脂缩醛磷脂（Pls）在大脑中含量丰富，据报道可通过增强神经元细胞中Akt和ERK信号通路的磷酸化来预防神经元细胞死亡。尽管发现Akt和ERK的激活对神经元细胞存活是必要的，但尚不清楚Pls如何增强细胞信号传导。为了回答这个问题，我们寻找神经元特异性孤儿G蛋白偶联受体（GPCR）蛋白，因为这些蛋白被认为在通过脂筏的细胞信号转导中起作用，在脂筏中发现Pls和一些GPCR都很丰富。在本研究中泛GPCR抑制剂显著降低了神经元细胞中Pls诱导ERK信号传导，表明Pls可以激活GPCR来诱导信号传导。然后我们检查了19种孤儿GPCR的mRNA表达，发现其中10种在神经元细胞中高表达。通过短发夹（sh）-RNA慢病毒颗粒敲低这10种神经元特异性GPCR，发现在GPR1、GPR19、GPR21、GPR27和GPR61敲低的细胞中，Pls介导的ERK磷酸化受到抑制。我们进一步发现这些GPCR的过表达增强了细胞中Pls介导的ERK和Akt磷酸化。最有趣的是，当内源性Pls减少时，GPCR介导的细胞信号传导显著降低。我们的累积数据首次提示了Pls在神经系统中诱导细胞信号传导的可能机制。
