Levey A I
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13541-6. doi: 10.1073/pnas.93.24.13541.
Cholinergic transmission at muscarinic acetylcholine receptors (mAChR) has been implicated in higher brain functions such as learning and memory, and loss of synapses may contribute to the symptoms of Alzheimer disease. A heterogeneous family of five genetically distinct mAChR subtypes differentially modulate a variety of intracellular signaling systems as well as the processing of key molecules involved in the pathology of the disease. Although many muscarinic effects have been identified in memory circuits, including a diversity of pre- and post-synaptic actions in hippocampus, the identities of the molecular subtypes responsible for any given function remain elusive. All five mAChR genes are expressed in hippocampus, and subtype-specific antibodies have enabled identification, quantification, and localization of the encoded proteins. The m1, m2, and m4 mAChR proteins are most abundant in forebrain regions and they have distinct cellular and subcellular localizations suggestive of various pre- and postsynaptic functions in cholinergic circuits. The subtypes are also differentially altered in postmortem brain samples from Alzheimer disease cases. Further understanding of the molecular pharmacology of failing synapses in Alzheimer disease, together with the development of new subtype-selective drugs, may provide more specific and effective treatments for the disease.
毒蕈碱型乙酰胆碱受体（mAChR）处的胆碱能传递与学习和记忆等高级脑功能有关，突触丧失可能导致阿尔茨海默病的症状。由五个基因不同的mAChR亚型组成的异质家族差异调节多种细胞内信号系统以及参与该疾病病理过程的关键分子的加工。尽管在记忆回路中已发现许多毒蕈碱样作用，包括海马体中多种突触前和突触后的作用，但负责任何特定功能的分子亚型的身份仍然难以捉摸。所有五个mAChR基因均在海马体中表达，亚型特异性抗体已能够对编码蛋白进行鉴定、定量和定位。m1、m2和m4 mAChR蛋白在前脑区域最为丰富，它们具有不同的细胞和亚细胞定位，提示胆碱能回路中各种突触前和突触后的功能。在阿尔茨海默病病例的死后脑样本中，这些亚型也有不同程度的改变。进一步了解阿尔茨海默病中功能失调突触的分子药理学，以及开发新的亚型选择性药物，可能为该疾病提供更具体、有效的治疗方法。
