Biological functions of mammalian non-pacreatic type Phospholipase A_2

已知哺乳动物细胞具有几种类型的磷脂酶A2。在大鼠腹膜肥大细胞中检测到一定量的II组磷脂酶A2。结果发现，这种酶在细胞受到刺激后会分泌到培养基中。II组磷脂酶A2的抑制剂显著抑制肥大细胞的脱颗粒和类二十烷酸的产生。这些观察结果可能表明这种类型的磷脂酶A2在脱颗粒过程的进展中起作用。分子量为85kDa的胞质磷脂酶A2被认为是生产类二十烷和白三烯的限速酶。我们发现该酶不仅具有磷脂酶A2活性，而且具有溶血磷脂酶活性。与花生四烯酸释放同时产生的溶血磷脂对细胞具有毒性，因为它具有清洁剂的性质。胞质内85kDa磷脂酶A2可能通过其固有的溶血磷脂酶活性清除这些脂质。与上文提到的Ca2+依赖性磷脂酶A2不同，我们从哺乳动物大脑中发现了Ca2+非依赖性磷脂酶A2。此外，我们还成功地对该酶进行了纯化和cDNA克隆。出乎意料的是，其中一个亚基的编码基因与米勒-迪克无脑畸形的致病基因完全相同。该遗传性综合征可导致早期平滑脑的形成和死亡，提示细胞内磷脂酶可能在中枢神经系统的发育中起重要作用。

Mammalian cells are known to posseces several type of phospholipase A2. Group II phospholipase A2 was detected in appreciable amounts in rat perioneal mast cells. It was found that the enzyme was is secreted into medium upon stimulation of the cells. The degranulation and eicosanoid production by mast cells are significantly suppressed by the inhibitors of group II phospholipase A2. These observation may suggest that this type of phospholipase A2 play an role in the progression of the degranulation process. A cytosolic phospholipiase A2 with a molecular weight of 85kDa is thought to be a rate limiting enzyme for the production of eicosanoids and leukotrienes. We have discovered that the enzyme has not only phospholipase A2 activity but also lysophospholipase activity. The lysophospholipids produced concomitant with the relase of arachidonaic acid is toxic to the cells because of its detergent-like nature. The cytosolic 85kDa phospholipase A2 may scavenge such lipids by its intrinsic lysophospholipiase activity.Instead of Ca2+-dependent phospholipase A2 as mentioned above, we have discovered Ca2+-independent phospholipase A2 from mammalian brain. Moreover, we have succeeded in purification and cDNA cloning of the enzyme Unexpectedly, the gene encoding fothe one of the subunit is identical with the causative gene for the Miller-Dieker lissencephaly. This inherited syndrome caused a formation of smooth brain and a death in early age These results suggest that intrascellular phospholipase may play an essental role in the development of central nervous system.