TESTS OF THE ROLES OF 2 DIFFUSIBLE SUBSTANCES IN LONG-TERM POTENTIATION - EVIDENCE FOR NITRIC-OXIDE AS A POSSIBLE EARLY RETROGRADE MESSENGER
TESTS OF THE ROLES OF 2 DIFFUSIBLE SUBSTANCES IN LONG-TERM POTENTIATION - EVIDENCE FOR NITRIC-OXIDE AS A POSSIBLE EARLY RETROGRADE MESSENGER
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DOI：
10.1073/pnas.88.24.11285
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发表时间：
1991-12-01
影响因子：
11.1
通讯作者：
ARANCIO, O
中科院分区：
文献类型：
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作者：
ODELL, TJ;HAWKINS, RD;ARANCIO, O
尽管海马 CA1 区的长时程增强 (LTP) 是由 Ca2+ 通过 N-甲基-D-天冬氨酸受体通道流入突触后启动的，但 LTP 的维持似乎至少部分是在突触前进行的。这表明突触后细胞释放逆行信使来激活突触前末梢。该信使很可能是膜渗透性的，并通过扩散到达突触前神经元。因此，我们研究了两种主要的膜渗透候选逆行信使：花生四烯酸和一氧化氮（NO）。与花生四烯酸或脂氧合酶代谢物作为逆行信使一致，磷脂酶 A2 和脂氧合酶抑制剂去甲二氢愈创木酸在体外阻断了豚鼠 CA1 区的 LTP。然而，花生四烯酸（高达 100-mu-M）并不能可靠地产生活性无关的 LTP，并且花生四烯酸的活性依赖性增强作用被 DL-氨基磷酸戊酸阻断。由于去甲二氢愈创木酸也会干扰涉及 NO 的信号转导，因此我们接下来检查了 NO 合酶抑制剂是否会阻断 LTP。 N(G)-硝基-L-精氨酸在浴中给予时可阻断 LTP，并且这种抑制作用可被高浓度的 L-精氨酸部分克服，表明该抑制剂对 NO 合酶具有特异性。当细胞内注射时，N(G)-硝基-L-精氨酸和 N(G)-甲基-L-精氨酸（但不是 N(G)-甲基-D-精氨酸）也能阻断 LTP，表明 NO 合酶位于突触后细胞中。反过来，NO 似乎被释放到细胞外空间，因为用血红蛋白（一种与 NO 结合且不被细胞吸收的蛋白质）浸泡切片也会阻断 LTP。此外，NO 还能增强离解细胞培养物中海马神经元自发突触前释放的递质。这些数据支持这样的观点：NO 可能是 LTP 中的逆行信使。
Although long-term potentiation (LTP) in the CA1 region of the hippocampus is initiated postsynaptically by the influx of Ca2+ through N-methyl-D-aspartate receptor channels, the maintenance of LTP seems to be at least in part presynaptic. This suggests that the postsynaptic cell releases a retrograde messenger to activate the presynaptic terminals. It is likely that this messenger is membrane-permeant and reaches the presynaptic neuron by diffusion. We therefore have investigated two major membrane-permeant candidate retrograde messengers, arachidonic acid and nitric oxide (NO). Consistent with arachidonic acid or a lipoxygenase metabolite being a retrograde messenger, the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid blocked LTP in the guinea pig CA1 region in vitro. However, arachidonic acid (up to 100-mu-M) did not reliably produce activity-independent LTP, and activity-dependent potentiation by arachidonic acid was blocked by DL-aminophosphonovaleric acid. Since nordihydroguaiaretic acid also interferes with signal transduction involving NO, we next examined whether inhibitors of NO synthase block LTP. N(G)-Nitro-L-arginine blocked LTP when given in the bath, and this inhibition was partially overcome by high concentrations of L-arginine, suggesting that the inhibitor is specific to NO synthase. N(G)-Nitro-L-arginine and N(G)-methyl-L-arginine (but not N(G)-methyl-D-arginine) also blocked LTP when injected intracellularly, indicating that NO synthase is located in the postsynaptic cell. The NO, in turn, seems to be released into the extracellular space, since bathing the slice with hemoglobin, a protein that binds NO and is not taken up by cells, also blocked LTP. Moreover, NO enhances spontaneous presynaptic release of transmitter from hippocampal neurons in dissociated cell culture. These data favor the idea that NO might be a retrograde messenger in LTP.