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人胰淀素(hAmylin)是由分泌胰岛素的胰岛B细胞释放,作用于靶组织,维持细胞的兴奋性和葡萄糖在体内的稳态。hAmylin分泌异常会引起人类的疾病,特别是阿尔茨海默氏病(Alzheimer’s disease,AD)。目前对于hAmylin通过激活什么样的受体从而产生脑神经元的神经毒性仍然不清楚。已知烟碱乙酰胆碱受体(nicotinic acetylcholine receptors,nAChRs)是引发多种神经性疾病的关键因素。本研究通过记录hAmylin和烟碱对基底前脑神经元的全细胞电流和膜电位的影响,来确定hAmylin受体和烟碱受体两者之间的相互作用。在酶解分离的基底前脑Broca区(diagonal band of Broca,DBB)胆碱能神经元上进行全细胞膜片钳记录,结果显示,hAmylin或烟碱单独应用,均引起剂量(1nmol/L~20μmol/L)依赖性膜电位的去极化和DBB神经元放电频率增加。hAmylin受体拮抗剂AC253,不仅阻断hAmylin的兴奋作用,而且也阻断烟碱对神经元的兴奋作用;同样,使用nAChR竞争性拮抗剂二氢-β-刺桐啶碱(dihydro-β-erythroidine,DHβE),可以阻断烟碱和hAmylin对DBB神经元的兴奋作用。以上结果提示,hAmylin受体和nAChRs受体在DBB神经元可能是功能偶联的,协同影响DBB神经元的兴奋性。
Human amylin (hAmylin) is released by insulin-secreting pancreatic islet B cells and acts on target tissues to maintain cellular excitability and glucose homeostasis. Abnormal secretion of hAmylin can cause diseases in humans, especially Alzheimer’s disease (AD). The neurotoxicity of brain neurons that hAmylin activates by activating receptors remains unclear. Nicotinic acetylcholine receptors (nAChRs) are known to be key contributors to a variety of neurological diseases. In this study, the effects of hAmylin and nicotine on whole cell currents and membrane potential in basal forebrain neurons were recorded to determine the interaction between hAmylin receptor and nicotinic receptor. Whole-cell patch-clamp recordings were performed on cholinergic neurons in the basal forebrain Broca area (DBB) of the enzymatically isolated and isolated basal forebrain. The results showed that both hAmylin and nicotine alone resulted in a dose-dependent (1 nmol / L ~ 20 μmol / L) -dependent membrane potential depolarization and DBB neuron firing frequency increase. hAmylin receptor antagonist AC253, not only blocked the excitatory effect of hAmylin, but also blocked the excitatory effect of nicotine on neurons. Similarly, nAChR, a competitive antagonist of dihydro-β-seminar, erythroidine, DHβE), can block the excitatory effects of nicotine and hAmylin on DBB neurons. The above results suggest that hAmylin receptor and nAChRs receptors may be functionally coupled in DBB neurons and synergistically affect the excitability of DBB neurons.