Chan Guy C-K, Tonegawa Susumu, Storm Daniel R
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2005 Oct 26;25(43):9913-8. doi: 10.1523/JNEUROSCI.2376-05.2005.
Ca2+-stimulated adenylyl cyclases are important for several forms of neuroplasticity because they couple activity-dependent Ca2+ increases to cAMP in neurons. For example, the calmodulin-stimulated adenylyl cyclases, AC1 and AC8, are required for hippocampus-dependent memory and long-lasting long-term potentiation. To identify other mechanisms for Ca2+ stimulation of adenylyl cyclases, cultured hippocampal neurons from transgenic mice lacking both AC1 and AC8 [double knock-out (DKO) mice] were analyzed for Ca2+ stimulation of intracellular cAMP. Surprisingly, neurons from DKO mice showed significant Ca2+-stimulated cAMP accumulation that was blocked by inhibitors of calcineurin [PP2B (protein phosphatase 2B)], a Ca2+-activated protein phosphatase. Analysis of cultured neurons from calcineurin(-/-) mice confirmed that hippocampal neurons exhibit a calcineurin-dependent cAMP increase, which may contribute to some forms of neuroplasticity.
钙离子刺激的腺苷酸环化酶对多种形式的神经可塑性很重要,因为它们将神经元中依赖于活动的钙离子增加与环磷酸腺苷(cAMP)偶联起来。例如,钙调蛋白刺激的腺苷酸环化酶AC1和AC8是海马体依赖的记忆和持久的长时程增强所必需的。为了确定钙离子刺激腺苷酸环化酶的其他机制,对来自缺乏AC1和AC8的转基因小鼠[双敲除(DKO)小鼠]的培养海马神经元进行了细胞内cAMP的钙离子刺激分析。令人惊讶的是,DKO小鼠的神经元显示出显著的钙离子刺激的cAMP积累,而这种积累被钙调神经磷酸酶[PP2B(蛋白磷酸酶2B)]的抑制剂所阻断,钙调神经磷酸酶是一种钙离子激活的蛋白磷酸酶。对来自钙调神经磷酸酶基因敲除小鼠的培养神经元的分析证实,海马神经元表现出依赖于钙调神经磷酸酶的cAMP增加,这可能有助于某些形式的神经可塑性。