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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The β_(1a) subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle
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The β_(1a) subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

机译：β_（1a）亚基对于骨骼肌中二氢吡啶受体阵列的组装至关重要

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摘要

Homozygous zebrafish of the mutant relaxed (red~(ts25)) are paralyzed and die within days after hatching. A significant reduction of intramembrane charge movements and the lack of depolarization-induced but not caffeine-induced Ca~(2+) transients suggested a defect in the skeletal muscle dihydropyridine receptor (DHPR). Sequencing of DHPR cDNAs indicated that the α_(1S) subunit is normal, whereas the β_(1a) subunit harbors a single point mutation resulting in a premature stop. Quantitative RT-PCR revealed that the mutated gene is transcribed, but Western blot analysis and immunocytochemistry demonstrated the complete loss of the β_(1a) protein in mutant muscle. Thus, the immotile zebrafish relaxed is a β_(1a)-null mutant. Interestingly, immunocytochemistry showed correct triad targeting of the β_(1a) subunit in the absence of β_(1a). Freeze-fracture analysis of the DHPR clusters in relaxed myotubes revealed an ≈2-fold reduction in cluster size with a normal density of DHPR particles within the clusters. Most importantly, DHPR particles in the junctional membranes of the immotile zebrafish mutant relaxed entirely lacked the normal arrangement in arrays of tetrads. Thus, our data indicate that the lack of the β_(1a) subunit does not prevent triad targeting of the DHPR α_(1S) subunit but precludes the skeletal muscle-specific arrangement of DHPR particles opposite the ryanodine receptor (RyR1). This defect properly explains the complete deficiency of skeletal muscle excitation-contraction coupling in β_1-null model organisms.
机译：突变的纯合斑马鱼（红色〜（ts25））瘫痪，在孵化后数天内死亡。膜内电荷运动的显着减少和缺乏去极化诱导而不是咖啡因诱导的Ca〜（2+）瞬变提示骨骼肌二氢吡啶受体（DHPR）的缺陷。 DHPR cDNA的测序表明α_（1S）亚基是正常的，而β_（1a）亚基则具有单点突变，导致过早终止。定量RT-PCR揭示了突变的基因已被转录，但Western印迹分析和免疫细胞化学表明突变肌肉中β_（1a）蛋白完全丢失。因此，放松的不动的斑马鱼是一个β_（1a）-null突变体。有趣的是，免疫细胞化学显示在不存在β_（1a）的情况下，β_（1a）亚基的三联体靶向正确。 DHPR簇在松弛的肌管中的冷冻断裂分析表明，簇大小减小了约2倍，而簇中的DHPR颗粒的密度正常。最重要的是，不动的斑马鱼突变体的接合膜中的DHPR颗粒完全缺乏四分体排列中的正常排列。因此，我们的数据表明，缺乏β_（1a）亚基并不能阻止DHPRα_（1S）亚基的三联体靶向，但会排除与ryanodine受体（RyR1）对立的DHPR颗粒的骨骼肌特异性排列。该缺陷适当地解释了β_1-无模型生物中骨骼肌兴奋-收缩偶联的完全缺陷。

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