Calmodulin (CaM) regulation of Ca 2+ channels is central to Ca 2+ signaling. Ca V 1 versus Ca V 2 classes of these channels exhibit divergent forms of regulation, potentially relating to customized CaM/IQ interactions among different channels. Here we report the crystal structures for the Ca 2+ /CaM IQ domains of both Ca V 2.1 and Ca V 2.3 channels. These highly similar structures emphasize that major CaM contacts with the IQ domain extend well upstream of traditional consensus residues. Surprisingly, upstream mutations strongly diminished Ca V 2.1 regulation, whereas downstream perturbations had limited effects. Furthermore, our Ca V 2 structures closely resemble published Ca 2+ /CaM-Ca V 1.2 IQ structures, arguing against Ca V 1/2 regulatory differences based solely on contrasting CaM/IQ conformations. Instead, alanine scanning of the Ca V 2.1 IQ domain, combined with structure-based molecular simulation of corresponding CaM/IQ binding energy perturbations, suggests that the C lobe of CaM partially dislodges from the IQ element during channel regulation, allowing exposed IQ residues to trigger regulation via isoform-specific interactions with alternative channel regions.