Modulation of cardiac ryanodine receptor 2 by calmodulin

The high-conductance intracellular calcium (Ca²⁺) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators, calmodulin (CaM) regulates RyR2 in a Ca²⁺-dependent manner. Here we reveal the regulatory mechanism by which porcine RyR2 is modulated by human CaM through the structural determination of RyR2 under eight conditions. Apo-CaM and Ca²⁺-CaM bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical and central domains. The shift in CaM-binding sites on RyR2 is controlled by Ca²⁺ binding to CaM, rather than to RyR2. Ca²⁺-CaM induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95 and Ca²⁺-activated channel. By contrast, the pore of the ATP, caffeine and Ca²⁺-activated channel remains open in the presence of Ca²⁺-CaM, which suggests that Ca²⁺-CaM is one of the many competing modulators of RyR2 gating.