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Published 7 November 2005. doi:10.1083/jcb.200505155
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 3, 537-547
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Article

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

Andy Hudmon1, Howard Schulman1, James Kim3, Janet M. Maltez3, Richard W. Tsien2, and Geoffrey S. Pitt2,3,4,5

1 Department of Neurobiology, Stanford University, Stanford, CA 94305
2 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305
3 Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032
4 Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032
5 Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032

Correspondence to Richard W. Tsien: rwtsien{at}stanford.edu

Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for up-regulation 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 {alpha}1C (Cav{alpha}1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of {alpha}1C is essential for CDF of L-type channels. Ca2+ influx triggers distinct features of CaMKII targeting and activity. After Ca2+-induced targeting to {alpha}1C, 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.

A. Hudmon's present address is Dept. of Neurology, Yale University, New Haven, CT 06516.

H. Schulman's present address is SurroMed, Inc., Menlo Park, CA 94025.

Abbreviations used in this paper: AIP-2, autocamtide-2–related inhibitory peptide; AKAP, A-kinase anchor protein; CaMKII, Ca2+/calmodulin-dependent kinase II; CDF, Ca2+-dependent facilitation; CDI, Ca2+-dependent inactivation; HEK, human embryonic kidney; NMDAR, N-methyl-D-aspartate receptor; PKA, protein kinase A; Po, open probability; PP1, protein phosphatase 1.


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