Model for CDI and VDI. (A) Ca²⁺ channel at rest when no Ca²⁺ influx occurs. At rest, in the absence of Ca²⁺, the CaM binds to peptide A, located between the EF hand and the IQ motif of the C terminus of the L-VDCC α_1C subunit. In response to a depolarizing stimulus, Ca²⁺ enters through the L-VDCC and binds to CaM. In the open Ca²⁺ channel state, the EF hand prevents structural conformation of the I–II loop required to block Ca²⁺ entry through the channel pore (B). In addition, the hydrophobic I1654 in the IQ motif is a stabilizing factor preventing the occlusion of the pore. Upon elevation of [Ca²⁺]_i (depolarization), the Ca²⁺/CaM complex undergoes the Ca²⁺-dependent conformational change that relieves the inhibition of EF hand, permitting the I–II loop to interact with the pore and accelerate the fast inactivation process (C). The graph shows representative I_Ca traces evoked by depolarization from –50 mV to +40 mV, as labeled, using –60 mV as holding potential. (D) Involvement of CaM and CaMKII in the facilitation process. CaMKII enhances the I_Ca through phosphorylation of L-VDCC. We show murine whole-cell I_Ca generated from paired depolarizing pulses (–60 mV ± 10 mV at 0.5 Hz) representing Ca²⁺-dependent facilitation (graph).