Ster Jeanne, De Bock Frédéric, Guérineau Nathalie C, Janossy Andrea, Barrère-Lemaire Stéphanie, Bos Johannes L, Bockaert Joël, Fagni Laurent
Institute of Functional Genomics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5203, Institute National de la Santé et de la Recherche Médicale U661, Universités Montpellier I et II, 34095 Montpellier, France.
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2519-24. doi: 10.1073/pnas.0611031104. Epub 2007 Feb 6.
The exchange factor directly activated by cAMP (Epac) is a newly discovered direct target for cAMP and a guanine-nucleotide exchange factor for the small GTPase Rap. Little is known about the neuronal functions of Epac. Here we show that activation of Epac by specific cAMP analogs or by the pituitary adenylate cyclase-activating polypeptide induces a potent activation of the Ca2+-sensitive big K+ channel, slight membrane hyperpolarization, and increased after-hyperpolarization in cultured cerebellar granule cells. These effects involve activation of Rap and p38 MAPK, which mobilizes intracellular Ca2+ stores. These findings reveal a cAMP Epac-dependent and protein kinase A-independent signaling cascade that controls neuronal excitability.
由cAMP直接激活的交换因子（Epac）是新发现的cAMP直接作用靶点以及小GTP酶Rap的鸟嘌呤核苷酸交换因子。目前对Epac的神经元功能了解甚少。在此我们表明，通过特定的cAMP类似物或垂体腺苷酸环化酶激活多肽激活Epac，可在培养的小脑颗粒细胞中诱导Ca2+敏感的大K+通道的有效激活、轻微的膜超极化以及增强的超极化后电位。这些效应涉及Rap和p38丝裂原活化蛋白激酶的激活，从而动员细胞内Ca2+储备。这些发现揭示了一种控制神经元兴奋性的、依赖cAMP-Epac且独立于蛋白激酶A的信号级联反应。
