Interactions of cardiac L-type calcium channels with Calmodulin (CaM) strongly affect the inactivation kinetics of the respective Ca2+ currents. Putative CaM binding regions, among them an IQ motif, have been identified within the carboxyl terminal tail (C- term) of the cardiac isoform (a??1C ) of the dihydropyridine receptor. Despite the high degree of sequence homology between a?1C and the skeletal muscle isoform (a?1S ) at the putative CaM binding sites, a??1S lacks Ca2+ -dependent inactivation. We wondered whether the few differentially occupied amino acid positions at the proximal C-term could give rise to differences in the mode of CaM binding and, thus, contribute to the different time courses of Ca2+ -currents exhibited by a?1S and a?1C . We expressed and tested different regions of the a?1S or the a?1C C- term for their ability to form complexes with CaM using a) gel shift native PAGE in combination with mass spectrometry and b) fluorescence resonance energy transfer (FRET) in dysgenic myotubes. Surprisingly, C-term constructs of the skeletal muscle isoform failed to bind CaM, whereas the cardiac analogs robustly interacted with CaM, even at low basal [Ca2+ ]. Reciprocal exchanges of aberrant residues within the IQ motif attenuated CaM binding of the a?1C C-term constructs while they confered the abilty to bind CaM to the skeletal muscle constructs.