钾通道活动抑制与载脂蛋白E4引发的经由NMDA受体的钙超载有关.docVIP

  Potassium Channels Depression is involved in the Apolipoprotein E4 enhanced Calcium Influx via 5 10 15 N-Methyl-D-Aspartate receptor# Qin Ying1, Yang Lifan2, Weng Yuteng2, Luo Xiaoli2* (1. East Hospital, Tongji University School of Medicine, 200092; 2. Tongji University School of Medicine) Abstract: Among many suggested mechanisms of the association between the ε4 allele of apoplipoprotein E gene (APOE) and Alzheimer’s disease (AD), the present study focused on the link of apoE4 to Ca2+ homeostasis. On the acutely isolated hippocampal neurons, our observation showed that: 1) apoE4 increased the [Ca2+]i greatly and immediately. It was in a dose- and time- dependent manner, and irreversible; 2) removing Ca2+ from external solution abolished apoE4s effect on [Ca2+]i; 3) nicardipine showed little effect on apoE4-elicited [Ca2+]i increasing, while MK-801 almost blocked the apoE4-induced Ca2+ influx; and 4) pretreatment with K+ channel opener significantly reduced the apoE4-induced [Ca2+]i increasing. The results suggest that apoE4 increased [Ca2+]i by way of NMDA receptor channels but not L-type Ca2+ channels; and the depression of K+ channel activities was involved in this effects of apoE4. Key words: Apolipoprotein E4, calcium influx, potassium channel 20 0 Introduction Alzheimers disease (AD) is the leading cause of age-related dementia[1]. The APOE genotype is the strongest genetic factor of AD. It is reported that the risk of AD increases and the age of onset is earlier in late onset AD families with increasing number of APOE-ε4 alleles[2], which 25 30 35 suggests an important influence of the APOE ε4 genotype on the pathogenesis of AD. Physiologically, calcium is an important intracellular second messenger and controls a variety of neuronal functions. However, excessive intracellular calcium is associated with neurotoxicity [3-9], and hyperphosphorylation of tau[10, 11]. Therefore, apoE induced changes in calcium signaling could profoundly affect neuronal