Calmodulin kinase is a molecular switch for cardiac excitation-contraction coupling
Calmodulin kinase is a molecular switch for cardiac excitation-contraction coupling
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DOI：
10.1073/pnas.051449198
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发表时间：
2001-02-27
影响因子：
11.1
通讯作者：
Anderson, ME
中科院分区：
文献类型：
--
作者：
Wu, YJ;Colbran, RJ;Anderson, ME
肌浆网（SR）上细胞膜L型钙通道（LTCC）与Ryanodine受体钙释放通道（RyR）之间的信号传递是横纹肌兴奋-收缩偶联（ECC）的重要组成部分。骨骼肌中的LTCC和RyR之间存在物理联系，但在缺乏这种物理联系的心肌细胞中协调LTCC和RyR的分子机制尚不清楚。钙调素激酶（CaMK）具有适合ECC配位分子的特征：它被Ca 2 +/钙调素激活，调节LTCC和RyR，并且在LTCC和RyR附近富集。完整的心肌细胞进行了研究的条件下，CaMK的活性可以控制独立的细胞内Ca 2+，通过使用一个工程化的Ca 2+非依赖性形式的CaMK和一个高度特异性的CaMK抑制肽。CaMK可增强L-型Ca ~（2+）电流，减少SR的Ca ~（2+）释放，增加SR的Ca ~（2+）含量。这些研究结果支持的假设，CaMK是需要功能耦合LTCC和RyR在心脏ECC。
Signaling between cell membrane-bound L-type Ca2+ channels (LTCC) and ryanodine receptor Ca2+ release channels (RyR) on sarcoplasmic reticulum (SR) stores grades excitation-contraction coupling (ECC) in striated muscle. A physical connection regulates LTCC and RyR in skeletal muscle, but the molecular mechanism for coordinating LTCC and RyR in cardiomyocytes, where this physical link is absent, is unknown. Calmodulin kinase (CaMK) has characteristics suitable for an ECC coordinating molecule: it is activated by Ca2+/calmodulin, it regulates LTCC and RyR, and it is enriched in the vicinity of LTCC and RyR. Intact cardiomyocytes were studied under conditions where CaMK activity could be controlled independently of intracellular Ca2+ by using an engineered Ca2+-independent form of CaMK and a highly specific CaMK inhibitory peptide. CaMK reciprocally enhanced L-type Ca2+ current and reduced release of Ca2+ from the SR while increasing SR Ca2+ content. These findings support the hypothesis that CaMK is required to functionally couple LTCC and RyR during cardiac ECC.