Doxorubicin induces caspase-mediated proteolysis of KV7.1

K(v)7.1 (KCNQ1) coassembles with KCNE1 to generate the cardiac I(Ks)-channel. Gain- and loss-of-function mutations in KCNQ1 are associated with cardiac arrhthymias, highlighting the importance of modulating I(Ks) activity for cardiac function. Here, we report proteolysis of K(v)7.1 as an irreversible posttranslational modification. The identification of two C-terminal fragments of K(v)7.1 led us to identify an aspartate critical for the generation of one of the fragments and caspases as responsible for mediating proteolysis. Activating caspases reduces K(v)7.1/KCNE1 currents, which is abrogated in cells expressing caspase-resistant channels. Enhanced cleavage of K(v)7.1 can be detected for the LQT mutation G460S, which is located adjacent to the cleavage site, whereas a calmodulin-binding-deficient mutation impairs cleavage. Application of apoptotic stimuli or doxorubicin-induced cardiotoxicity provokes caspase-mediated cleavage of endogenous I(Ks) in human cardiomyocytes. In summary, caspases are novel regulatory components of I(Ks) channels that may have important implications for the molecular mechanism of doxorubicin-induced cardiotoxicity.