Ca2+ Stimulated Adenylyl Cyclases and Neuroplasticity

描述(申请人提供)：对记忆形成的细胞和分子基础有相当大的兴趣。对学习和记忆的研究对于更好地了解人类的认知障碍，包括阿尔茨海默氏症、自闭症、与衰老相关的记忆丧失和各种类型的精神发育迟缓具有重要的意义。这一假设的基本假设是，钙离子刺激CREB/CRE(cAMP反应元件)转录通路在长时程增强(L-LTP)和某些形式的海马区依赖的长时程记忆(LTM)中起着关键作用。我们的长期目标是明确钙离子刺激Cre介导的海马神经元转录的机制，并了解为什么这一途径的激活对LTM和L LTP具有重要意义。我们推测，钙激活Cre介导的转录需要ERK/MAPK和cAMP信号转导通路的共同激活。我们认为，关键的cAMP信号增加起源于钙调素刺激的腺酰环化酶的激活。我们推测，cAMP信号是ERK/MAPK核转位所必需的，也可能参与了ERK/MAPK的钙激活。我们还认为，Ras抑制剂SCOP的蛋白降解可能有助于激活和敏化Erk/MAPK信号转导通路。我们假设，海马区Cre介导的转录或转录振荡的长期增加可能是由于作为Erk/MAPK/Cre转录途径的正反馈调节因子的基因产物表达增加所致。

DESCRIPTION (provided by applicant): There is considerable interest in the cellular and molecular basis of memory formation. Studies of learning and memory are of fundamental importance for a better understanding of cognitive disorders in humans including Alzheimer's, autism, aging-related memory loss, and various types of mental retardation. It is the general hypothesis of this proposal that Ca2+ stimulation of the CREB/CRE (cAMP response element)-transcriptional pathway plays a pivotal role in long-lasting, long-term potentiation (L-LTP) and some forms of hippocampus-dependent long-term memory (LTM). Our long-term objectives are to define the mechanisms for Ca2+ stimulation of CRE-mediated transcription in hippocampal neurons and to understand why activation of this pathway is important for LTM and L-LTP. We hypothesize that Ca2+ activation of CRE-mediated transcription requires coactivation of the Erk/MAPK and camp signal transduction pathways. We propose that the critical cAMP signal increase originates from activation of calmodulin-stimulated adenylyl cyclases. We hypothesize that cAMP signaling is required for the nuclear translocation of Erk/MAPK and may also contribute to Ca2+ activation of Erk/MAPK. We also propose that proteolytic degradation of SCOP, a Ras inhibitor, may contribute to Ca2+ activation and sensitization of the Erk/MAPK signal transduction pathway. We hypothesize that long-lasting increases in CRE-mediated transcription, or transcriptional oscillations, in the hippocampus may be due to increased expression of gene products that function as positive-feedback regulators of the Erk/MAPK/CRE transcriptional pathway.