Wu Y, Colbran R J, Anderson M E
Department of Internal Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2877-81. doi: 10.1073/pnas.051449198.
Signaling between cell membrane-bound L-type Ca(2+) channels (LTCC) and ryanodine receptor Ca(2+) 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 Ca(2+)/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 Ca(2+) by using an engineered Ca(2+)-independent form of CaMK and a highly specific CaMK inhibitory peptide. CaMK reciprocally enhanced L-type Ca(2+) current and reduced release of Ca(2+) from the SR while increasing SR Ca(2+) content. These findings support the hypothesis that CaMK is required to functionally couple LTCC and RyR during cardiac ECC.
细胞膜结合的L型钙通道（LTCC）与肌浆网（SR）储存上的兰尼碱受体钙释放通道（RyR）之间的信号传导调节横纹肌中的兴奋-收缩偶联（ECC）。一种物理连接调节骨骼肌中的LTCC和RyR，但在不存在这种物理连接的心肌细胞中协调LTCC和RyR的分子机制尚不清楚。钙调蛋白激酶（CaMK）具有适合作为ECC协调分子的特性：它被Ca（2+）/钙调蛋白激活，调节LTCC和RyR，并且在LTCC和RyR附近富集。通过使用工程化的不依赖钙的CaMK形式和高度特异性的CaMK抑制肽，在可以独立于细胞内钙控制CaMK活性的条件下研究完整的心肌细胞。CaMK相互增强L型钙电流并减少SR中钙的释放，同时增加SR钙含量。这些发现支持以下假设：在心脏ECC期间，CaMK是功能性连接LTCC和RyR所必需的。
