CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation

Andy Hudmon, Howard Schulman, James Kim, Janet M. Maltez, Richard W. Tsien, Geoffrey S. Pitt

Research output: Contribution to journalArticle

237 Scopus citations


Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for upregulation of Ca2+ influx during repeated membrane depolarization. CDF of L-type Ca2+ channels (Cav1.2) contributes to the positive force-frequency effect in the heart and is believed to involve the activation of Ca2+/calmodulin- dependent kinase II (CaMKII). How CaMKII is activated and what its substrates are have not yet been determined. We show that the pore-forming subunit α1C (Cavα1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of α1C is essential for CDF of L-type channels. Ca2+ influx triggers distinct features of CaMKII targeting and activity. After Ca2+-induced targeting to α1C, CaMKII becomes tightly tethered to the channel, even after calcium returns to normal levels. In contrast, activity of the tethered CaMKII remains fully Ca2+/CaM dependent, explaining its ability to operate as a calcium spike frequency detector. These findings clarify the molecular basis of CDF and demonstrate a novel enzymatic mechanism by which ion channel gating can be modulated by activity.

Original languageEnglish (US)
Pages (from-to)537-547
Number of pages11
JournalJournal of Cell Biology
Issue number3
StatePublished - Nov 7 2005

ASJC Scopus subject areas

  • Cell Biology

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