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Molecular Basis of Calmodulin Tethering and Ca2+-dependent Inactivation of L-type Ca2+ Channels

Ca 2+ -dependent inactivation (CDI) of L-type Ca 2+ channels plays a critical role in controlling Ca 2+ entry and downstream signal transduction in excitable cells. Ca 2+ -insensitive forms of calmodulin (CaM) act as dominant negatives to prevent CDI, suggesting that CaM acts as a resident Ca 2+ sen...

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Published in:The Journal of biological chemistry 2001-08, Vol.276 (33), p.30794-30802
Main Authors: Pitt, G S, Zühlke, R D, Hudmon, A, Schulman, H, Reuter, H, Tsien, R W
Format: Article
Language:English
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Summary:Ca 2+ -dependent inactivation (CDI) of L-type Ca 2+ channels plays a critical role in controlling Ca 2+ entry and downstream signal transduction in excitable cells. Ca 2+ -insensitive forms of calmodulin (CaM) act as dominant negatives to prevent CDI, suggesting that CaM acts as a resident Ca 2+ sensor. However, it is not known how the Ca 2+ sensor is constitutively tethered. We have found that the tethering of Ca 2+ -insensitive CaM was localized to the C-terminal tail of α 1C , close to the CDI effector motif, and that it depended on nanomolar Ca 2+ concentrations, likely attained in quiescent cells. Two stretches of amino acids were found to support the tethering and to contain putative CaM-binding sequences close to or overlapping residues previously shown to affect CDI and Ca 2+ -independent inactivation. Synthetic peptides containing these sequences displayed differences in CaM-binding properties, both in affinity and Ca 2+ dependence, leading us to propose a novel mechanism for CDI. In contrast to a traditional disinhibitory scenario, we suggest that apoCaM is tethered at two sites and signals actively to slow inactivation. When the C-terminal lobe of CaM binds to the nearby CaM effector sequence (IQ motif), the braking effect is relieved, and CDI is accelerated.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M104959200