Postulated role of interdomain interaction within the ryanodine receptor in Ca2+ channel regulation
Postulated role of interdomain interaction within the ryanodine receptor in Ca2+ channel regulation
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DOI：
10.1074/jbc.275.16.11618
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发表时间：
2000-04-21
影响因子：
4.8
通讯作者：
Ikemoto, N
中科院分区：
文献类型：
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作者：
Yamamoto, T;El-Hayek, R;Ikemoto, N
恶性高热（MH）和中央核心疾病（CCD）的N-末端和中央结构域的兰尼碱受体的突变的局部分布表明，这些结构域之间的相互作用可能参与钙离子通道的调节。为了验证这一假设，我们研究了一个新的合成结构域肽DP 4对应的Leu（2442）-Pro（2477）区域的中央结构域的影响。DP 4增强ryanodine结合并诱导快速的Ca 2+释放。在DP 4存在下，激动剂的半数最大激活浓度显著降低。DP 4的这些作用类似于MH/CCD突变引起的兰尼碱受体的功能修饰（即通道的超活化和通道对激动剂的超敏）。用Cys替代DP 4的Arg，模拟体内Arg（2458）-至-Cys（2458）突变，消除了DP 4的活化作用，N-末端结构域肽DP 1（El-Hayek，R.，Saiki，Y.，山本，T.，和Ikemoto，N.（1999）J.Biol.Chem.274，33341-33347）显示出类似的活化/敏化作用。DP 4和DP 1的加入使它们的激活功能产生相互干扰。我们初步提出，两个（N-末端和中央）域之间的接触关闭的通道，而去除这些域肽或MH/CCD突变的接触解除封锁的通道，导致超活化/超敏效应。
Localized distribution of malignant hyperthermia (MH) and central core disease (CCD) mutations in N-terminal and central domains of the ryanodine receptor suggests that the interaction between these domains may be involved in Ca2+ channel regulation. To test this hypothesis, we investigated the effects of a new synthetic domain peptide DP4 corresponding to the Leu(2442)-Pro(2477) region of the central domain. DP4 enhanced ryanodine binding and induced a rapid Ca2+ release. The concentration for half-maximal activation by agonists was considerably reduced in the presence of DP4. These effects of DP4 are analogous to the functional modifications of the ryanodine receptor caused by MH/CCD mutations (viz. hyperactivation of the channel and hypersensitization of the channel to agonists). Replacement of Arg of DP4 with Cys, mimic-king the in vivo Arg(2458)-to-Cys(2458) mutation, abolished the activating effects of DP4, An N-terminal domain peptide DP1 (El-Hayek, R., Saiki, Y., Yamamoto, T., and Ikemoto, N. (1999) J. Biol. Chem. 274, 33341-33347) shows similar activation/sensitization effects. The addition of both DP4 and DP1 produced mutual interference of their activating functions. We tentatively propose that contact between the two (N-terminal and central) domains closes the channel, whereas removal of the contact by these domain peptides or by MH/CCD mutations deblocks the channel, resulting in hyperactivation/hypersensitization effects.