Nickel block of a family of neuronal calcium channels: Subtype- and subunit-dependent action at multiple sites

被引:177
作者
Zamponi, GW [1 ]
Bourinet, E [1 ]
Snutch, TP [1 ]
机构
[1] UNIV BRITISH COLUMBIA,BIOTECHNOL LAB,VANCOUVER,BC V6T 1Z3,CANADA
关键词
beta subunit; divalent cation; metal ion; gating charge; barium current;
D O I
10.1007/s002329900059
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nickel ions have been reported to exhibit differential effects on distinct subtypes of voltage-activated calcium channels. To more precisely determine the effects of nickel, we have investigated the action of nickel on four classes of cloned neuronal calcium channels (alpha(1A), alpha(1B), alpha 1C, and alpha(1E)) transiently expressed in Xenopus oocytes. Nickel caused two major effects: (i) block detected as a reduction of the maximum slope conductance and (ii) a shift in the current-voltage relation towards more depolarized potentials which was paralleled by a decrease in the slope of the activation-curve. Block followed 1:1 kinetics and was most pronounced for alpha(1C) followed by alpha(1E) > alpha(1A) > alpha(1B) channels. In contrast, the change in activation-gating was most dramatic with alpha(1E) with the remaining channel subtypes significantly less affected. The current-voltage shift was well described by a simple model in which nickel binding to a saturable site resulted in altered gating behavior. The affinity for both the blocking site and the putative gating site were reduced with increasing concentration of external permeant ion. Replacement of barium with calcium reduced both the degree of nickel block and the maximal effect on gating for alpha(1A) channels, but increased the nickel blocking affinity for alpha(1E) channels. The coexpression of Ca channel beta subunits was found to differentially influence nickel effects on alpha(1A), as coexpression with beta(2a) or with beta(4) resulted in larger current-voltage shifts than those observed in the presence of beta(1b), while elimination of the beta subunit almost completely abolished the gating shifts. In contrast, block was similar for the three beta subunits tested, while complete removal of the beta subunit resulted in an increase in blocking affinity. Our data suggest that the effect of nickel on calcium channels is complex, cannot be described by a single site of action, and differs qualitatively and quantitatively among individual subtypes and subunit combinations.
引用
收藏
页码:77 / 90
页数:14
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