Schuman E M, Meffert M K, Schulman H, Madison D V
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, CA 94305-5426.
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11958-62. doi: 10.1073/pnas.91.25.11958.
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.
近期对海马体CA1区长期增强作用（LTP）的研究表明，一氧化氮（NO）可能参与某些形式的LTP，并提示突触后生成的NO可能是一种逆行信使。然而，NO在LTP中的分子靶点仍有待阐明。本研究检测了两种潜在的NO靶点，可溶性鸟苷酸环化酶或ADP-核糖基转移酶（ADPRT；EC 2.4.2.31）是否在LTP中发挥作用。应用可透过细胞膜的cGMP类似物并未对突触强度产生任何持久的改变。此外，应用cGMP依赖性蛋白激酶抑制剂并不能阻止LTP。我们发现，海马体的CA1组织具有ADPRT活性，该活性可被NO显著激活，并被单-ADPRT活性的两种不同抑制剂，叶绿醌和烟酰胺所减弱。细胞外应用这些相同的抑制剂可阻止LTP。突触后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部位。这些结果表明ADP-核糖基化在LTP中发挥作用，并且与ADPRT可能是NO作用靶点的观点一致。
