Dihydropyridine receptors (DHPRs) and ryanodine receptors (RyRs) interact during EC coupling within calcium release units, CRUs. The location of the two channels and their positioning are related to their role in EC coupling. als DHPR and RyR1 of skeletal muscle form interlocked arrays. Groups of four DHPRs (forming a tetrad) are located on alternate RyR1s. This association provides the structural framework for reciprocal signaling between the two channels. RyR3 are present in some skeletal muscles in association with RyR1 and in ratios up to 1:1. RyR3 neither induce formation of tetrads by DHPRs nor sustain EC coupling. RyR3 are located in a parajunctional position, in proximity of the RyR1-DHPR complexes, and they may be indirectly activated by calcium liberated via the RyR1 channels. RyR2 have two locations in cardiac muscle. One is at CRUs that contain DHPRs and RyRs. In these cardiac CRUs, RyR2 and a1c DHPR are in proximity of each other, but not closely linked, so that they may not have a direct molecular interaction. A second location of RyR2 is on SR cisternae that are not attached to surface membrane/T tubules. The RyR2 in these cisternae, which are often several microns away from any DHPRs, must necessarily be activated indirectly.