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 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.
CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation
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.
Andy Hudmon, Howard Schulman, James Kim, Janet M. Maltez, Richard W. Tsien, Geoffrey S. Pitt; CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation . J Cell Biol 7 November 2005; 171 (3): 537–547. doi: https://doi.org/10.1083/jcb.200505155
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