title: Engineered calmodulins reveal the unexpected eminence of Ca2+ channel inactivation in controlling heart excitation.
abstract: Engineered calmodulins (CaMs), rendered Ca2+-insensitive by mutations, function as dominant negatives in heterologous systems, and have revealed mechanisms of ion channel modulation by Ca2+/CaM. The use of these CaMs in native mammalian cells now emerges as a strategy to unmask the biology of such Ca2+ feedback. Here, we developed recombinant adenoviruses bearing engineered CaMs to facilitate their expression in adult heart cells, where Ca2+ regulation may be essential for moment-to-moment control of the heartbeat. Engineered CaMs not only eliminated the Ca2+-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.
authors.affiliation: Calcium Signals Laboratory, Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Badr A
authors.initials: BA
authors.lastname: Alseikhan
authors.forename: Carla D
authors.initials: CD
authors.lastname: DeMaria
authors.forename: Henry M
authors.initials: HM
authors.lastname: Colecraft
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002147:Calmodulin / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D015202:Protein Engineering; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D002147:Calmodulin; D011994:Recombinant Proteins