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/转位的PKCd与其底物蛋白的偶联来保护心肌细胞免受缺血/再灌注损伤的假说。我们发现JTV519促进了PKCd的易位，而抑制了PKCd激活位点的磷酸化。此外，JTV519还将转位的PKCd结合到Annexin V的疏水部分。结果表明，Annexin V是胞液间隙中未折叠/激活的PKC的载体蛋白，JTV519可能阻止该载体蛋白释放激活的PKC。这些数据为调节亚细胞空间中的关键酶活性，如PKCd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.