Excitation-contraction (e-c) coupling in muscle cells is a mechanism that allows transduction of exterior-membrane depolarization in Ca2+ release from the Sarcoplasmic Reticulum (SR). The communication between external and internal membranes is possible thanks to the interaction between Dihydropyridine Receptors (DHPRs), voltage-gated Ca2+ channels located in exterior membranes, and Ryanodine Receptors (RyRs), the Ca2+ release channels of the SR. In both skeletal and cardiac muscle cells the key structural element that allows DHPRs and RyRs to interact with each other is their vicinity. However, the signal that the two molecules use to communicate is not the same in the two muscle types. In the heart, the inward flux of Ca2+ through DHPRs, that follows depolarization, triggers the opening of RyRs (calcium induced calcium release). In skeletal muscle, on the other hand, Ca2+ is not needed for RyRs activation; instead the coupling between the two molecules involves a direct link between them (mechanical coupling). Ultrastructural studies show that functional differences can be explained by differences in the DHPR/RyR reciprocal association: whereas the two proteins are very close to each other in both muscles, DHPRs form tetrads only in skeletal fibers. Tetrads represent the structural DHPR/RyR link that allows Ca2+ independent coupling in skeletal muscle.