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

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 (Ca_v1.2) 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 α_1C (Ca_vα1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of α_1C is essential for CDF of L-type channels. Ca²⁺ influx triggers distinct features of CaMKII targeting and activity. After Ca²⁺-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 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.