Lu Yun-Fei, Hawkins Robert D
Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
J Neurophysiol. 2002 Sep;88(3):1270-8. doi: 10.1152/jn.2002.88.3.1270.
We previously found that the nitric oxide (NO)-cGMP-cGMP-dependent protein kinase (PKG) signaling pathway acts in parallel with the cAMP-cAMP-dependent protein kinase (PKA) pathway to produce protein and RNA synthesis-dependent late-phase long-term potentiation (L-LTP) and cAMP response element-binding protein (CREB) phosphorylation in the CA1 region of mouse hippocampus. We have now investigated the possible involvement of a downstream target of PKG, ryanodine receptors. L-LTP can be induced by either multiple-train tetanization, NO or 8-Br-cGMP paired with one-train tetanization, or the cAMP activator forskolin, and all three types of potentiation are accompanied by an increase in phospho-CREB immunofluorescence in the CA1 cell body area. Both the potentiation and the increase in phospho-CREB immunofluorescence induced by multiple-train tetanization or 8-Br-cGMP paired with one-train tetanization are reduced by prolonged perfusion with ryanodine, which blocks Ca(2+) release from ryanodine-sensitive Ca(2+) stores. By contrast, neither the potentiation nor the increase in immunofluorescence induced by forskolin are reduced by depletion of ryanodine and inositol-1,4,5-triphosphate (IP3)-sensitive Ca(2+) stores. These results suggest that NO, cGMP, and PKG cause release of Ca(2+) from ryanodine-sensitive stores, which in turn causes phosphorylation of CREB in parallel with PKA during the induction of L-LTP.
我们之前发现，一氧化氮（NO）-环鸟苷酸（cGMP）-cGMP依赖性蛋白激酶（PKG）信号通路与环磷酸腺苷（cAMP）-cAMP依赖性蛋白激酶（PKA）通路并行发挥作用，以在小鼠海马体CA1区产生蛋白质和RNA合成依赖性的晚期长时程增强（L-LTP）以及环磷酸腺苷反应元件结合蛋白（CREB）磷酸化。我们现在研究了PKG的下游靶点——兰尼碱受体可能的参与情况。L-LTP可由多串强直刺激、NO或8-溴-cGMP与单串强直刺激配对诱导产生，也可由cAMP激活剂福斯可林诱导产生，并且所有这三种类型的增强都伴随着CA1细胞体区域磷酸化CREB免疫荧光的增加。多串强直刺激或8-溴-cGMP与单串强直刺激配对诱导的增强以及磷酸化CREB免疫荧光的增加，在长时间灌注兰尼碱后均会降低，兰尼碱可阻断从兰尼碱敏感的Ca(2+)储存库释放Ca(2+)。相比之下，福斯可林诱导的增强和免疫荧光增加均不会因兰尼碱和肌醇-1,4,5-三磷酸（IP3）敏感的Ca(2+)储存库耗尽而降低。这些结果表明，NO、cGMP和PKG会导致从兰尼碱敏感储存库释放Ca(2+)，进而在L-LTP诱导过程中与PKA并行导致CREB磷酸化。
