Mashimo Masato, Hirabayashi Tetsuya, Murayama Toshihiko, Shimizu Takao
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan.
J Cell Sci. 2008 Sep 15;121(Pt 18):3015-24. doi: 10.1242/jcs.032987. Epub 2008 Aug 19.
Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) selectively releases arachidonic acid from membrane phospholipids and has been proposed to be involved in the induction of long-term depression (LTD), a form of synaptic plasticity in the cerebellum. This enzyme requires two events for its full activation: Ca(2+)-dependent translocation from the cytosol to organelle membranes in order to access phospholipids as substrates, and phosphorylation by several kinases. However, the subcellular distribution and activation of cPLA(2)alpha in Purkinje cells and the role of arachidonic acid in cerebellar LTD have not been fully elucidated. In cultured Purkinje cells, stimulation of AMPA receptors, but not metabotropic glutamate receptors, triggered translocation of cPLA(2)alpha to the somatic and dendritic Golgi compartments. This translocation required Ca(2+) influx through P-type Ca(2+) channels. AMPA plus PMA, a chemical method for inducing LTD, released arachidonic acid via phosphorylation of cPLA(2)alpha. AMPA plus PMA induced a decrease in surface GluR2 for more than 2 hours. Interestingly, this reduction was occluded by a cPLA(2)alpha-specific inhibitor. Furthermore, PMA plus arachidonic acid caused the prolonged internalization of GluR2 without activating AMPA receptors. These results suggest that cPLA(2)alpha regulates the persistent decrease in the expression of AMPA receptors, underscoring the role of cPLA(2)alpha in cerebellar LTD.
胞质型磷脂酶A2α（cPLA2α）可从膜磷脂中选择性释放花生四烯酸，有人提出它参与了长时程抑制（LTD）的诱导，LTD是小脑突触可塑性的一种形式。该酶的完全激活需要两个事件：依赖钙离子从胞质转运至细胞器膜以接触磷脂作为底物，以及被多种激酶磷酸化。然而，浦肯野细胞中cPLA2α的亚细胞分布和激活情况以及花生四烯酸在小脑LTD中的作用尚未完全阐明。在培养的浦肯野细胞中，刺激AMPA受体而非代谢型谷氨酸受体可触发cPLA2α向胞体和树突状高尔基体区室的转运。这种转运需要钙离子通过P型钙离子通道内流。AMPA加佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA，一种诱导LTD的化学方法）通过cPLA2α的磷酸化释放花生四烯酸。AMPA加PMA可使表面GluR2减少超过2小时。有趣的是，这种减少被cPLA2α特异性抑制剂阻断。此外，PMA加花生四烯酸导致GluR2的长时间内化而不激活AMPA受体。这些结果表明cPLA2α调节AMPA受体表达的持续减少，强调了cPLA2α在小脑LTD中的作用。
