ALZHEIMER-DISEASE AMYLOID BETA-PROTEIN FORMS CALCIUM CHANNELS IN BILAYER-MEMBRANES - BLOCKADE BY TROMETHAMINE AND ALUMINUM
ALZHEIMER-DISEASE AMYLOID BETA-PROTEIN FORMS CALCIUM CHANNELS IN BILAYER-MEMBRANES - BLOCKADE BY TROMETHAMINE AND ALUMINUM
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DOI：
10.1073/pnas.90.2.567
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发表时间：
1993-01-15
影响因子：
11.1
通讯作者：
POLLARD, HB
中科院分区：
文献类型：
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作者：
ARISPE, N;ROJAS, E;POLLARD, HB
淀粉样β蛋白(AbetaP)是一种由40-42个残基组成的多肽，与阿尔茨海默病的发病机制有关。我们已经将该多肽结合到磷脂酰丝氨酸脂质体中，然后将脂质体与平面双层融合。当AbetaP被结合到双层中时，它形成沟道，在对称的溶液中产生线性电流-电压关系。根据通道电流在不对称KCl溶液中的反转电位，估算出开放的AbetaP通道的渗透率比P(K)/P(Cl)为11。不同阳离子的渗透率顺序为P(Cs)&Gt；P(Li)&Gt；P(Ca)大于或等于P(K)&Gt；P(Na)。AbetaP通道电流(Cs+或Ca~(2+)作为电荷载体)可被氨丁三醇(毫摩尔范围)可逆地阻断，而被Al3+(微摩尔范围)不可逆地阻断。这两种物质对AbetaP通道电流的抑制依赖于跨膜电位，提示其阻断机制涉及氨丁三醇(或Al3+)与AbetaP通道内的位点之间的直接相互作用。到目前为止，AbetaP一直被认为是神经毒性的。根据目前的数据，我们认为多肽的通道活性可能是其部分或全部神经毒性作用的原因。我们进一步建议，治疗阿尔茨海默病的药物发现的有用策略可能包括筛选化合物阻断或以其他方式修改AbetaP通道的能力。
Amyloid beta protein (AbetaP) is the 40- to 42-residue polypeptide implicated in the pathogenesis of Alzheimer disease. We have incorporated this peptide into phosphatidylserine liposomes and then fused the liposomes with a planar bilayer. When incorporated into bilayers the AbetaP forms channels, which generate linear current-voltage relationships in symmetrical solutions. A permeability ratio, P(K)/P(Cl), Of 11 for the open AbetaP channel was estimated from the reversal potential of the channel current in asymmetrical KCl solutions. The permeability sequence for different cations, estimated from the reversal potential of the AbetaP-channel current for each system of asymmetrical solutions, is P(Cs) > P(Li) > P(Ca) greater-than-or-equal-to P(K) > P(Na). AbetaP-channel current (either Cs+ or Ca2+ as charge carriers) is blocked reversibly by tromethamine (millimolar range) and irreversibly by Al3+ (micromolar range). The inhibition of the AbetaP-channel current by these two substances depends on transmembrane potential, suggesting that the mechanism of blockade involves direct interaction between tromethamine (or Al3+) and sites within the AbetaP channel. Hitherto, AbetaP has been presumed to be neurotoxic. On the basis of the present data we suggest that the channel activity of the polypeptide may be responsible for some or all of its neurotoxic effects. We further propose that a useful strategy for drug discovery for treatment of Alzheimer disease may include screening compounds for their ability to block or otherwise modify AbetaP channels.