CaMKII tethers to L-type Ca(2+) channels, establishing a local and dedicated integrator of Ca(2+) signals for facilitation

Ca(2+)-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for up-regulation of Ca(2+) influx during repeated membrane depolarization. CDF of L-type Ca(2+) channels (Ca(v)1.2) contributes to the positive force–frequency effect in the heart and is believed to involve the activation of Ca(2+)/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 α(1C) (Ca(v)α1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of α(1C) is essential for CDF of L-type channels. Ca(2+) influx triggers distinct features of CaMKII targeting and activity. After Ca(2+)-induced targeting to α(1C), CaMKII becomes tightly tethered to the channel, even after calcium returns to normal levels. In contrast, activity of the tethered CaMKII remains fully Ca(2+)/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.