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首页> 外文期刊>Biochemistry >Regulation of the RYR1 and RYR2 Ca~(2+) Release Channel Isoforms by Ca~(2+)-Insensitive Mutants of Calmodulin
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Regulation of the RYR1 and RYR2 Ca~(2+) Release Channel Isoforms by Ca~(2+)-Insensitive Mutants of Calmodulin

机译：Ca〜（2+）不敏感的钙调蛋白突变体对RYR1和RYR2 Ca〜（2+）释放通道亚型的调节

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Calmodulin (CaM) may function as a regulatory subunit of ryanodine receptor (RYR) channels, modulating both channel activation and inhibition by Ca~(2+); however, mechanisms underlying differences in CaM regulation of the RYR isoforms expressed in skeletal muscle (RYR1) and cardiac muscle (RYR2) are poorly understood. Here we use a series of CaM mutants deficient in Ca~(2+) binding to compare determinations of CaM regulation of the RYR1 and RYR2 isoforms. In submicromolar Ca~(2+), activation of the RYR1 isoform by each of the single-point CaM mutants was similar to that by wild-type apoCaM, whereas in micromolar Ca~(2+), RYR1 inhibition by Ca~(2+) CaM was abolished by mutations targeting CaM's C-terminal Ca~(2+) sites. In contrast to the RYR1, no activation of the cardiac RYR2 isoform by wild-type CaM was observed, but rather CaM inhibited the RYR2 at all Ca~(2+) concentrations (100 nM to 1 mM). Consequently, whereas the apparent Ca~(2+) sensitivity of the RYR1 isoform was enhanced in the presence of CaM, the RYR2 displayed the opposite response (RYR2 Ca~(2+) EC_(50) increased 7-10-fold in the presence of 5 muM wild-type CaM). CaM inhibition of the RYR2 was nonetheless abolished by each of four mutations targeting individual CaM Ca~(2+) sites. Furthermore, a mutant CaM deficient in Ca~(2+) binding at all four Ca~(2+) sites significantly activated the RYR2 and acted as a competitive inhibitor of RYR2 regulation by wild-type Ca~(2+)CaM. We conclude that Ca~(2+) binding to CaM determines the effect of CaM on both RYR1 and RYR2 channels and that isoform differences in CaM regulation reflect the differential tuning of Ca~(2+) binding sites on CaM when bound to the different RYRs. These results thus suggest a novel mechanism by which CaM may contribute to functional diversity among the RYR isoforms.
机译：钙调蛋白（CaM）可能作为ryanodine受体（RYR）通道的调节亚基，通过Ca〜（2+）调节通道激活和抑制。然而，人们对在骨骼肌（RYR1）和心肌（RYR2）中表达的RYR亚型的CaM调节差异的潜在机制了解甚少。在这里，我们使用一系列缺乏Ca〜（2+）结合的CaM突变体来比较RYR1和RYR2亚型的CaM调控测定。在亚微摩尔Ca〜（2+）中，每个单点CaM突变体对RYR1亚型的激活与野生型apoCaM相似，而在微摩尔Ca〜（2+）中，Ca〜（2）对RYR1的抑制作用+）CaM被针对CaM的C末端Ca〜（2+）位点的突变所废除。与RYR1相反，未观察到野生型CaM对心脏RYR2亚型的激活，但CaM在所有Ca〜（2+）浓度（100 nM至1 mM）下均抑制了RYR2。因此，尽管在CaM存在下RYR1亚型的表观Ca〜（2+）敏感性增强，但RYR2显示出相反的响应（RYR2 Ca〜（2+）EC_（50）在CaM中增加了7-10倍。存在5μM野生型CaM）。然而，针对单个CaM Ca〜（2+）位点的四个突变均消除了对RYR2的CaM抑制作用。此外，在所有四个Ca〜（2+）位点均缺乏Ca〜（2+）结合的突变型CaM显着激活了RYR2，并成为野生型Ca〜（2+）CaM对RYR2调控的竞争性抑制剂。我们得出的结论是，Ca〜（2+）与CaM的结合决定了CaM对RYR1和RYR2通道的影响，并且CaM调控中的同工型差异反映了当Ca〜（2+）与不同位置结合时，CaM（2+）结合位点的差异性RYRs。因此，这些结果表明，CaM可能有助于RYR同工型之间功能多样性的新机制。

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