This study examined the bindings of calmodulin (CaM) and its mutants with the C- and N-terminal tails of the voltage-gated Ca(2+) channel CaV1.2 at different CaM and Ca(2+) concentrations ([Ca(2+)]) by using the pull-down assay method to obtain basic information on the binding mode, including its concentration- and Ca(2+)-dependencies. Our data show that more than one CaM molecule could bind to the CaV1.2 C-terminal tail at high [Ca(2+)]. Additionally, the C-lobe of CaM is highly critical in sensing the change of [Ca(2+)] in its binding to the C-terminal tail of CaV1.2, and the binding between CaM and the N-terminal tail of CaV1.2 requires high [Ca(2+)]. Our data provide new details on the interactions between CaM and the CaV1.2 channel.