An ADP-ribosyltransferase as a potential target for nitric oxide action in hippocampal long-term potentiation.

Recent studies of long-term potentiation (LTP) in the CA1 region of the hippocampus have demonstrated that nitric oxide (NO) may be involved in some forms of LTP and have suggested that postsynaptically generated NO is a candidate to act as a retrograde messenger. However, the molecular target(s) of NO in LTP remain to be elucidated. The present study examined whether either of two potential NO targets, a soluble guanylyl cyclase or an ADP-ribosyltransferase (ADPRT; EC 2.4.2.31) plays a role in LTP. The application of membrane-permeant analogs of cGMP did not produce any long-lasting alterations in synaptic strength. In addition, application of a cGMP-dependent protein kinase inhibitor did not prevent LTP. We found that the CA1 tissue from hippocampus possesses an ADPRT activity that is dramatically stimulated by NO and attenuated by two different inhibitors of mono-ADPRT activity, phylloquinone and nicotinamide. The extracellular application of these same inhibitors prevented LTP. Postsynaptic injection of nicotinamide failed to attenuate LTP, suggesting that the critical site of ADPRT activity resides at a nonpostsynaptic locus. These results suggest that ADP-ribosylation plays a role in LTP and are consistent with the idea that an ADPRT may be a target of NO action. IMAGES:

针对海马体CA1区域长时程增强（long-term potentiation，LTP）的近期研究表明，一氧化氮（nitric oxide，NO）可能参与部分类型的LTP，并提示突触后产生的NO可作为逆行信使的候选物质。然而，NO在LTP中的分子靶标仍有待阐明。本研究探究了两种潜在的NO靶标——可溶性鸟苷酸环化酶与ADP核糖基转移酶（ADP-ribosyltransferase，ADPRT；EC 2.4.2.31）是否在LTP中发挥作用。应用膜通透型环磷酸鸟苷（cyclic guanosine monophosphate，cGMP）类似物并未对突触强度产生任何长效改变。此外，应用cGMP依赖性蛋白激酶抑制剂也未能阻断LTP。我们发现，海马CA1组织具有ADPRT活性，该活性可被NO显著激活，并可被两种不同的单ADPRT活性抑制剂——叶绿醌与烟酰胺所减弱。上述抑制剂的胞外应用均可阻断LTP。而突触内注射烟酰胺未能减弱LTP，这表明ADPRT活性的关键位点位于非突触后区域。上述结果提示，ADP核糖基化在LTP中发挥作用，且与ADPRT可能是NO作用靶标的观点相一致。IMAGES: