Portal de Periódicos da CAPES

Engineered calmodulins reveal the unexpected eminence of Ca 2+ channel inactivation in controlling heart excitation

2002; National Academy of Sciences; Volume: 99; Issue: 26 Linguagem: Inglês

10.1073/pnas.262372999

1091-6490

Badr A. Alseikhan, Carla D. DeMaria, Henry M. Colecraft, David T. Yue,

Receptor Mechanisms and Signaling

Engineered calmodulins (CaMs), rendered Ca 2+ -insensitive by mutations, function as dominant negatives in heterologous systems, and have revealed mechanisms of ion channel modulation by Ca 2+ /CaM. The use of these CaMs in native mammalian cells now emerges as a strategy to unmask the biology of such Ca 2+ feedback. Here, we developed recombinant adenoviruses bearing engineered CaMs to facilitate their expression in adult heart cells, where Ca 2+ regulation may be essential for moment-to-moment control of the heartbeat. Engineered CaMs not only eliminated the Ca 2+ -dependent inactivation of native calcium channels, but exposed an unexpectedly large impact of removing such feedback: the unprecedented (4- to 5-fold) prolongation of action potentials. This striking result recasts the basic paradigm for action-potential control and illustrates the promise of virally delivered engineered CaM to investigate the biology of numerous other CaM-signaling pathways.