Piomelli D, Wang J K, Sihra T S, Nairn A C, Czernik A J, Greengard P
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021.
Proc Natl Acad Sci U S A. 1989 Nov;86(21):8550-4. doi: 10.1073/pnas.86.21.8550.
A variety of evidence indicates that activation of Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) in nerve terminals leads to enhanced neurotransmitter release. Arachidonic acid and its 12-lipoxygenase metabolite, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), have been suggested to act as second messengers mediating presynaptic inhibition of neurotransmitter release. In the present study it was found that CaM-kinase II, purified from rat brain cortex, was inhibited both by arachidonic acid (IC50 = 24 microM) and by 12-HPETE (IC50 = 0.7 microM). Neither substance inhibited CaM-kinase I or III, protein kinase C, or the catalytic subunit of cAMP-dependent protein kinase. Specific inhibition of Ca2+/calmodulin-dependent protein phosphorylation by arachidonic acid was also demonstrated in intact synaptic terminals (synaptosomes) isolated from rat forebrain. These results suggest that arachidonate and its metabolites may modulate synaptic function through the inhibition of CaM-kinase II-dependent protein phosphorylation.
多种证据表明，神经末梢中钙/钙调蛋白依赖性蛋白激酶II（CaM激酶II）的激活会导致神经递质释放增强。花生四烯酸及其12-脂氧合酶代谢产物12-氢过氧化二十碳四烯酸（12-HPETE）被认为可作为介导神经递质释放突触前抑制的第二信使。在本研究中发现，从大鼠脑皮质纯化的CaM激酶II受到花生四烯酸（IC50 = 24 microM）和12-HPETE（IC50 = 0.7 microM）的抑制。这两种物质均未抑制CaM激酶I或III、蛋白激酶C或cAMP依赖性蛋白激酶的催化亚基。在从大鼠前脑分离的完整突触终末（突触体）中也证实了花生四烯酸对钙/钙调蛋白依赖性蛋白磷酸化的特异性抑制。这些结果表明，花生四烯酸及其代谢产物可能通过抑制CaM激酶II依赖性蛋白磷酸化来调节突触功能。
