In skeletal muscle cells, dihydropyridine receptors (DHPR) of the transverse tubules (TT) and ryanodine receptors (RyR1) of the sarcoplasmic reticulum (SR) exhibit bidirectional conformational interaction. Orthograde DHPR-RyR1 coupling forms the basis of the voltage-activated Ca2+ release that controls muscle force, whereas retrograde RyR1-DHPR coupling upregulates the DHPR-mediated high voltage-activated L-type Ca2+ inward current. RyR1 appears to also affect DHPR inactivation because muscle cells of malignant hyperthermia-susceptible (MHS) mice expressing mutant RyR1 (Y524S) showed a negative shift in the voltage of half-maximal L-type current availability. Here, we investigated the hypothesis that elevated calcium levels in the TT-SR junctional gap resulting from the hyperactive mutant RyR1 modify DHPR inactivation. We studied voltage-controlled Ca2+ release and Ca2+ inward current in enzymatically isolated adult muscle fibers of WT mice and of heterozygous Y524S+/- mice. Millimolar concentrations of caffeine that favor RyR1 open probability led to a left shift in the voltage-dependent availability curve for L-type current in WT muscle fibers, similar to the effect of the MHS mutation. Thus drug-induced RyR1 hyperactivity mimics the effect of the mutation. However, the difference between WT and Y524S+/- fibers was insensitive to fiber dialysis with an artificial solution containing a high concentration of BAPTA to stabilize the junctional free calcium concentration. Combined, these results suggest that the open RyR1 conformation rather than resulting junctional Ca2+ leads to the observed changes in DHPR inactivation.