Diversity of amyloid β protein fragment [1-40]-formed channels
Diversity of amyloid β protein fragment [1-40]-formed channels
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DOI：
10.1023/a:1010995121153
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发表时间：
2001-06-01
影响因子：
4
通讯作者：
Farrelly, P
中科院分区：
文献类型：
--
作者：
Kourie, JI;Henry, CL;Farrelly, P
1.用脂质双层技术研究了淀粉样β蛋白片段(AβP)1-40掺入脂膜形成的几种离子通道的生物物理和药理性质。根据电导、动力学、选择性和药理学特性，已确定了以下AβP[1-40]形成的离子通道：(I)AβP[1-40]形成的快速阳离子通道的特征是：(A)单通道电导在+140 mV时为63ps(250/50 mmKClcis/tran)，在-160 mV时为17pS(250/50mmKc/cis/tran)，并绘制了三次多项式的非线性电流-电压关系，(B)选择性序列P-K>；P-Na>；P-Li=1.0：0.60：0.47，(C)在0 mV时P-o为0.22，在+120 mV时为0.55，以及(D)锌离子引起的电流幅度降低，这是一种典型的慢阻断机制。(Ii)AβP[1-40]形成的“尖峰”快速阳离子通道的特征是：(A)动力学类似于“突发性”快速通道，只是没有长的突发性闭合，(B)+140 mV、17pS(250/50kCI)、-160 mV时的单通道电导为63ps(250/50kCi)，电流-电压关系符合三次多项式，以及(C)选择性序列P-Rb>；P-K>；P-Cs>；P-Na>；P-Li=1.3：1.0：0.46：0.40：027。(Iii)AβP[1-40]形成的中等电导通道在+140 mV时为275ps(250/50 mmKCL顺式/反式)，在-160 mV时为19pS(250/50 mMKClcis/tras)，(B)在V(M)S为负值时比-120 mV时失活，在+120 mV时为正值。(4)AβP[1-40]形成的失活大电导通道的特性通过(A)在+140 mV时开通0-589 ps(在250/50 mm KCl中)和在-160 mV时在0-704 ps(在250/50 mm KCI中)之间的7个多电平电导的快模式和慢模式，(B)电导为250ps的快速模式也依赖于电压。(C)快模式的P-K/P-胆碱值为3.9，选择性顺序为P-K>；F-Cs>；P-Na>；P-Li=1.0：0.94：0.87：0.59。吹扫模式下的P-K/P-胆碱值为2.7，选择性顺序为P-K>；P-Na>；P-Li>；P-Cs=1.0：0.59：0.49：0.21。大电导通道的快模不受10 mM锌离子的影响。有人提出，尽管“爆发式”快速通道、“尖峰”快速通道和失活的中等电导通道是不同的，但它们可能是另一种构型的中间构型，这些构型是失活的大电导通道的基础。这种异质性被认为是这些带正电的细胞毒素淀粉样蛋白形成的通道最常见的特征之一，反映了这些通道改变多种细胞功能的能力。此外，基于β-折叠的寡聚体的形成可能是形成细胞毒性淀粉样蛋白通道的一个重要的共同步骤。
1. The lipid bilayer technique was used to characterize the biophysical and pharmacological properties of several ion channels formed by incorporating amyloid beta protein fragment (A betaP) 1-40 into lipid membranes. Based on the conductance, kinetics, selectivity, and pharmacological properties, the following A betaP [1-40]-formed ion channels have been identified:(i) The A betaP[1-40]-formed "bursting" fast cation channel was characterized by (a) a single channel conductance of 63 pS (250/50 mM KCl cis/trans) at +140 mV, 17 pS (250/50 mM KC/ cis/trans) at -160 mV, and the nonlinear current-voltage relationship drawn to a third-order polynomial, (b) selectivity sequence P-K>P-Na>P-Li = 1.0:0.60:0.47, (c) P-o of 0.22 at 0 mV and 0.55 at +120 mV, and (d) Zn2+-induced reduction in current amplitude, a typical property of a slow block mechanism.(ii) The A betaP[1-40]-formed "spiky" fast cation channel was characterized by (a) a similar kinetics to the "bursting" fast channel with exception for the absence of the long intraburst closures, (b) single channel conductance of 63 pS (250/50 KCI) at +140 mV 17 pS (250/50 KCI) at -160 mV, the current-voltage relationship nonlinear drawn to a third-order polynomial fit, and (c) selectivity sequence P-Rb>P-K>P-Cs>P-Na>P-Li = 1.3:1.0:0.46:0.40:027.(iii) The A betaP[1-40]-formed medium conductance channel was characterized by (a) 275 pS (250/50 mM KCL cis/trans) at +140 mV and 19 pS (250/50 mM KCl cis/trans) at -160 mV and (b) inactivation at V(m)s more negative than -120 and more positive than + 120 mV.(iv) The A betaP[1-40] -formed inactivating large conductance channel was characterized by (a) fast and slow modes of opening to seven multilevel conductances ranging between 0-589 pS (in 250/50 mM KCl) at +140 mV and 0-704 pS (in 250/50 mM KCI) at -160 mV, (b)The fast mode which had a conductance of 250 pS was also voltage dependent. The inactivation was described by a bell-shaped curve with a peak lag time of 7.0 s at -76 mV, (c) the value of P-K/P-choline for the fast mode was 3.9 and selectivity sequence P-K>F-Cs>P-Na>P-Li = 1.0:0.94:0.87:0.59. The value of P-K/P-choline for the blow mode was 2.7 and selectivity sequence P-K>P-Na>P-Li>P-Cs = 1.0:0.59:0.49:0.21, and (d) asymmetric blockade with 10 mM Zn2+-induced reduction in the large conductance state of the slow mode mediated via slow block mechanism. The fast mode of the large conductance channel was not affected by 10 mM Zn2+.2. It has been suggested that, although the "bursting" fast channel, the "spiky" fast channel and the inactivating medium conductance channel are distinct, it is possible that they are intermediate configurations of yet another configuration underlying the inactivating large conductance channel. It is proposed that this heterogeneity is one of the most common features of these positively-charged cytotoxic amyloid-formed channels reflecting these channels ability to modify multiple cellular functions.3. Furthermore, the formation of beta -sheet based oligomers could be an important common step in the formation of cytotoxic amyloid channels.