Fig. 1.

Modulation of the ryanodine receptor (RyR) by Ca²⁺ and phosphorylation. Ca²⁺ influx via the L-type Ca channel (LTCC) activates the RyR and triggers Ca²⁺ release from the sarcoplasmic reticulum (SR), a process referred to as Ca²⁺ induced Ca²⁺ release or CICR, leading to myocyte contraction. The levels of free cytosolic Ca²⁺ are tightly regulated by the SR Ca²⁺ ATPase (SERCA) and the sarcolemmal Na⁺-Ca²⁺ exchanger (not indicated). After CICR and contraction, the Ca²⁺ store is refilled by pumping Ca²⁺ back into the SR thereby re-establishing diastolic Ca²⁺ levels. The sensitivity of RyR toward activating Ca²⁺ is modulated by phosphorylation. Stimulation of the β₁-adrenoreceptor (β-AR) leads to Gs-protein-mediated activation of adenylyl cyclase (AC) and further cAMP-dependent activation of PKA. PKA can directly phosphorylate RyR at several phosphorylation sites, presumably at S2808, possibly inducing dissociation of calstabin 2, and at S2030, but also modulates the LTCC and SERCA function, the latter by phosphorylation of phospholamban (PLB). Increased cytosolic Ca²⁺ levels activate CaMKII, which directly phosphorylates RyR at S2814. Similar to PKA, CaMKII also phosphorylates PLB and the LTCC leading to global changes in myocyte Ca²⁺ homeostasis.