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

Geoffrey S. Pitt, Roger D. Zühlke, Andy Hudmon, Howard Schulman, Harald Reuter, Richard W. Tsien

Research output: Contribution to journalArticle

233 Scopus citations

Abstract

Ca2+-dependent inactivation (CDI) of L-type Ca2+ channels plays a critical role in controlling Ca2+ entry and downstream signal transduction in excitable cells. Ca2+-insensitive forms of calmodulin (CaM) act as dominant negatives to prevent CDI, suggesting that CaM acts as a resident Ca2+ sensor. However, it is not known how the Ca2+ sensor is constitutively tethered. We have found that the tethering of Ca2+-insensitive CaM was localized to the C-terminal tail of α1C, close to the CDI effector motif, and that it depended on nanomolar Ca2+ 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 Ca2+-independent inactivation. Synthetic peptides containing these sequences displayed differences in CaM-binding properties, both in affinity and Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)30794-30802
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number33
DOIs
StatePublished - Aug 17 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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