Molecular contraction of Ca^<2+> signaling

在可兴奋的细胞中，细胞表膜的去极化信号通过细胞内的钙离子储存被转化为胞质内的钙信号。我研究的最终目标是了解信号转换机制的分子结构，在这个项目中，我重点研究了兰诺定受体作为细胞内钙释放通道的功能，以及细胞内钙离子储存的分子组成。在对Ryanodine受体的实验中，已经在一级结构上定位了一个用于通道失活的Ca~(2+)和G~(2+)结合部位，并在骨骼肌细胞中确定了三联体连接中Ryanodine受体亚型的共存。另一方面，目前已经发现了新的膜蛋白--丝裂胶蛋白。Mitsugum29是syanptophisin家族中的一个新成员，具有4个跨膜片段。当骨骼肌细胞缺乏丝裂原29时，三联体连接不能正确构建，从而降低了兴奋-收缩偶联的效率。连接素(Mitsugum72)由识别细胞表膜的细胞质区域和跨越Ca~(2+)储存膜的跨膜片段组成。当心肌细胞缺乏连接素时，细胞表面膜与钙库之间的连接膜结构发育不良，导致细胞内钙信号异常，导致胚胎期心力衰竭。

In excitable cells, the depolarization signal of cell-surface membrane is converted into cytoplasmic Ca^<2+> signaling using intracellular Ca^<2+> stores. The final goal of my study is to understand the molecular architecture of the signal conversion machinery, and in this project I focused on the function of the ryanodine receptor as an inracellular Ca^<2+> release channel and the molecular components of intracellular Ca^<2+> stores. In experiments on the ryanodine receptor, a Ca^<2+>-binding site for channel inactivation has been mapped on the primary structure, and co-existence of ryanodine receptor subtypes in the triad junction has been defined in skeletal muscle cells. On the other hands, novel membrane proteins namely mitsugumins have been identified currently. Mitsugumin29 is a novel member of the syanptophisin family bearing 4 transmembrane segments. When skeletal muscle cells lacked mitsugumin29, triad junctions could not be constructed correctly and thus efficiency of excitation-contraction coupling reduced. Junctophilin (mitsugumin72) is composed of the cytoplasmic region recognizing the cell-surface membrane and the transmembrane segment spanning the Ca^<2+> store membrane. When cardiac muscle lacked junctophilin, junctional membrane structures between the cell-surface membrane and Ca^<2+> store were poorly developed and resulting abnormal Ca^<2+> signaling resulted in heart failure during embryonic stages.