Ca2+ Stimulated Adenylyl Cyclases and Neuroplasticity

描述（由申请人提供）：对记忆形成的细胞和分子基础有相当大的兴趣。学习和记忆的研究对于更好地理解人类的认知障碍，包括阿尔茨海默氏症、自闭症、与年龄相关的记忆丧失和各种类型的智力迟钝，具有至关重要的意义。这一提议的一般假设是，Ca2+刺激CREB/CRE （cAMP反应元件）-转录途径在长时、长时增强（L-LTP）和某些形式的海马体依赖性长时记忆（LTM）中起关键作用。我们的长期目标是确定Ca2+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很重要。我们假设Ca2+激活cre介导的转录需要Erk/MAPK和camp信号转导途径的共激活。我们认为cAMP信号的关键增加源于钙调素刺激的腺苷酸环化酶的激活。我们假设cAMP信号是Erk/MAPK核易位所必需的，也可能有助于Erk/MAPK的Ca2+激活。我们还提出，Ras抑制剂SCOP的蛋白水解降解可能有助于Ca2+激活和Erk/MAPK信号转导通路的敏化。我们假设，CRE介导的转录或转录振荡在海马体内的持续增加可能是由于Erk/MAPK/CRE转录途径的正反馈调节基因产物的表达增加。

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.