Isozyme-Specific Pharmacological Properties of Protein Kinase C and Approaches to New Drug Development

我们验证了JTV519通过抑制激活/易位PKCd与其底物蛋白的偶联来保护心肌细胞免受缺血/再灌注损伤的假设。我们发现JTV519促进PKCd的易位，而PKCd激活位点的磷酸化被抑制。此外，JTV519在膜联蛋白V的疏水部分结合易位PKCd。数据表明，膜联蛋白V是胞质空间中未折叠/活化的PKC的载体蛋白，JTV519可能阻断该载体蛋白释放活化的PKC。这些数据为调控亚细胞空间中PKCd等关键酶的活性提供了新的途径。

We tested hypothesis that JTV519 protects the cardiomyocytes from ischemia/reperfusion injury by inhibiting coupling of activated/translocated PKCd with its substrate proteins. We found that JTV519 facilitates translocation of PKCd while the phosphorylation of activation sites of PKCd is inhibited. Furthermore, JTV519 binds the translocated PKCd at a hydrophobic portion of annexin V. The data suggests that annexin V is a carrier protein of the unfoled/activated PKC in the cytosolic space and JTV519 may block the release of activated PKC from this carrier protein. The data provide the new approach to regulated the key enzyme activity such as PKCd in the subcellular space.