Key result
Doxorubicin induces caspase-mediated proteolysis of the Kv7.1 potassium channel at aspartate 459, which reduces Kv7.1/KCNE1 currents and may contribute to cardiotoxicity.
Doxorubicin induces caspase-mediated cleavage of Kv7.1 channels, reducing IKs currents, which may explain the molecular mechanism of doxorubicin-induced cardiotoxicity and arrhythmias.
May implicate Kv7.1 cleavage in preclinical doxorubicin cardiotoxicity; leaves open clinical relevance and therapeutic targeting.
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.
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Strigli et al. (2018) studied Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Vehicle was evaluated on Caspase-mediated cleavage of Kv7.1 (generation of CTF2 fragment). Doxorubicin induces caspase-mediated proteolysis of the Kv7.1 potassium channel at aspartate 459, which reduces Kv7.1/KCNE1 currents and may contribute to cardiotoxicity.
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