L-type Ca2+ current (ICa-L) triggers Ca2+ release from the sarcoplasmic reticulum (SR) and both SR and ICa-L are potential sources of intracellular Ca2+ (Ca2+i) for feedback regulation of ICa-L. Ca2+i bound to calmodulin (Ca2+/CaM) can inhibit ICa-L, while Ca2+/CaM can also activate Ca2+/CaM-dependent protein kinase II (CaMK) to increase ICa. However, it is unknown if ICa-L or the SR are the primary source of Ca2+ for ICa-L regulation. The L-type Ca2+ channel C terminus is implicated as a critical transduction element for ICa-L responses to Ca2+/CaM and CaMK, and the C terminus undergoes voltage- dependent steric changes, suggesting that Ca2+i control of ICa-L may also be regulated by cell membrane potential. We developed conditions to separately test the relationship of Ca2+/CaM and CaMK to ICa-L and SR Ca2+i release during voltage clamp conditions modeled upon time and voltage domains relevant to the cardiac action potential. Here we show that CaMK increases ICa- L after brief positive conditioning pulses, whereas Ca2+/CaM reduces ICa-L over a broad range of positive and negative conditioning potentials. SR Ca2+ release was required for both Ca2+/CaM and CaMK ICa-L responses after strongly positive conditioning pulses (+10 and +40 mV), while Ca2+i from ICa-L was sufficient for Ca2+/CaM during weaker depolarizations. These findings show that ICa-L responses to CaMK are voltage dependent and suggest a new model of L-type Ca2+ channel regulation where voltage-dependent changes control ICa-L responses to Ca2+/CaM and CaMK signaling.