Induction of hippocampal LTD requires nitric-oxide-stimulated PKG activity and Ca2+ release from cyclic ADP-ribose-sensitive stores.
Induction of hippocampal LTD requires nitric-oxide-stimulated PKG activity and Ca2+ release from cyclic ADP-ribose-sensitive stores.
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DOI：
10.1152/jn.1999.82.3.1569
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发表时间：
1999-09
影响因子：
2.5
通讯作者：
M. Reyes-Harde;Barry V. L. Potter;A. Galione;P. Stanton
中科院分区：
文献类型：
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作者：
M. Reyes-Harde;Barry V. L. Potter;A. Galione;P. Stanton
突触传递的长时程抑制（LTD）可由几种机制诱导，其中一种被认为涉及突触后一氧化氮（NO）合酶的Ca 2+依赖性激活和随后的NO向突触前末梢的扩散。我们使用稳定的NO供体S-亚硝基-N-乙酰青霉胺（SNAP）研究了体外Schaffer侧支-CA 1突触上NO依赖的LTD形式。SNAP（100 μ M）通过级联反应增强LTD的诱导，该级联反应被N-甲基-D-天冬氨酸受体拮抗剂D-2-氨基-5-膦酰基戊酸（50 μ M）、NO鸟苷酸环化酶抑制剂1H-[1，2，4]恶二唑并[4，3-a]喹喔啉-1-酮（10 μ M）和PKG抑制剂KT 5823（1 μ M）阻断。我们进一步表明，在没有SNAP的情况下由低频刺激诱导的LTD也被KT 5823或Rp-8-（4-氯苯硫基）-鸟苷3 '，5'-环状单硫代磷酸（10 μ M）、环状鸟苷3 '，5'单磷酸依赖性蛋白激酶（PKG）抑制剂以不同的作用机制阻断。此外，SNAP促进LTD被阻止时，从细胞内钙库的释放被兰尼碱（10 μ M）抑制。最后，两个细胞渗透性拮抗剂的环状ADP-核糖结合位点的兰尼定受体也能够阻止诱导的LTD。这些结果支持级联诱导的homosynaptic，NO依赖性LTD涉及鸟苷酸环化酶的激活，生产的鸟苷3 '，5'环磷酸和随后的PKG激活。这个过程有一个额外的要求释放钙离子从ryanodine敏感的商店，可能依赖于第二信使环ADP核糖。
Long-term depression (LTD) of synaptic transmission can be induced by several mechanisms, one thought to involve Ca2+-dependent activation of postsynaptic nitric oxide (NO) synthase and subsequent diffusion of NO to the presynaptic terminal. We used the stable NO donor S-nitroso-N-acetylpenicillamine (SNAP) to study the NO-dependent form of LTD at Schaffer collateral-CA1 synapses in vitro. SNAP (100 microM) enhanced the induction of LTD via a cascade that was blocked by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoic acid (50 microM), NO guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (10 microM), and the PKG inhibitor KT5823 (1 microM). We further show that LTD induced by low-frequency stimulation in the absence of SNAP also is blocked by KT5823 or Rp-8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate (10 microM), cyclic guanosine 3',5' monophosphate-dependent protein kinase (PKG) inhibitors with different mechanisms of action. Furthermore SNAP-facilitated LTD was blocked when release from intracellular calcium stores was inhibited by ryanodine (10 microM). Finally, two cell-permeant antagonists of the cyclic ADP-ribose binding site on ryanodine receptors also were able to block the induction of LTD. These results support a cascade for induction of homosynaptic, NO-dependent LTD involving activation of guanylyl cyclase, production of guanosine 3',5' cyclic monophosphate and subsequent PKG activation. This process has an additional requirement for release of Ca2+ from ryanodine-sensitive stores, perhaps dependent on the second-messenger cyclic ADP ribose.