Ca(V)1.1e is the voltage-gated calcium channel splice variant of embryonic skeletal muscle. It differs from the adult Ca(V)1.1a splice variant by the exclusion of exon 29 coding for 19 amino acids in the extracellular loop connecting transmembrane domains IVS3 and IVS4. Like the adult splice variant Ca(V)1.1a, the embryonic Ca(V)1.1e variant functions as voltage sensor in excitation-contraction coupling, but unlike Ca(V)1.1a it also conducts sizable calcium currents. Consequently, physiological or pharmacological modulation of calcium currents may have a greater impact in Ca(V)1.1e expressing muscle cells. Here, we analyzed the effects of L-type current modulators on whole-cell current properties in dysgenic (Ca(V)1.1-null) myotubes reconstituted with either Ca(V)1.1a or Ca(V)1.1e. Furthermore, we examined the physiological current modulation by interactions with the ryanodine receptor using a chimeric Ca(V)1.1e construct in which the cytoplasmic II-III loop, essential for skeletal muscle excitation-contraction coupling, has been replaced with the corresponding but nonfunctional loop from the Musca channel. Whereas the equivalent substitution in Ca(V)1.1a had abolished the calcium currents, substitution of the II-III loop in Ca(V)1.1e did not significantly reduce current amplitudes. This indicates that Ca(V)1.1e is not subject to retrograde coupling with the ryanodine receptor and that the retrograde coupling mechanism in Ca(V)1.1a operates by counteracting the limiting effects of exon 29 inclusion on the current amplitude. Pharmacologically, Ca(V)1.1e behaves like other L-type calcium channels. Its currents are substantially increased by the calcium channel agonist Bay K 8644 and inhibited by the calcium channel blocker nifedipine in a dose-dependent manner. With an IC50 of 0.37 mu M for current inhibition by nifedipine, Ca(V)1.1e is a potential drug target for the treatment of myotonic dystrophy. It might block the excessive calcium influx resulting from the aberrant expression of the embryonic splice variant Ca(V)1.1e in the skeletal muscles of myotonic dystrophy patients.