FIGURE 2.

Proposed pathways for inducing SR Ca²⁺ leak during β-adrenergic signaling and stretch in a ventricular cardiomyocyte. (A) β-AR raises cAMP levels via G_s-protein-dependent activation of AC that activates both PKA and Epac. PKA phosphorylates LTCC and PLB leading to more Ca²⁺ influx and faster uptake by SERCA into the SR. Epac activates nNOS and CaMKII via an PI3K and AkT signaling cascade promoting SR Ca²⁺ leak via RyR phosphorylation. The broken line indicates a cAMP and Epac-independent pathway for local activation of nNOS targeted to RyR in the dyad. RyR not coupled to LTCC in T-tubules are not modulated by CaMKII and nNOS. eNOS is localized to caveolae and exerts negative effects on LTCC during β-adrenergic stimulation. (B) Mechanotransduction involves ROS and NO for RyR activation. The ROS and NO pathway are independent and operate on different timescales via different mechanosensors. NOX2 produces ROS near RyR in the dyad increasing RyR activity possibly via oxidation of CaMKII. With a delay, nNOS is activated via an unknown mechanosensing mechanism. The enhanced SR Ca²⁺ leak promotes Ca²⁺ waves that activate a transient inward NCX current causing DAD. Caveolar eNOS is activated by stretch via PI3K-Akt and positively modulates EC coupling outside the dyad by mechanisms that are incompletely understood. See text for further details. AC, adenyl cyclase; β-AR, β-adrenergic receptor; cAMP, cyclic adenosine 3’,5’-monophosphate; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; EC, excitation contraction; DAD, delayed afterdepolarizations; eNOS, endothelial nitric oxide synthase; Epac, exchange protein activated by cAMP; LTCC, L-type Ca channel; NCX, Na⁺/Ca²⁺ exchanger; NO, nitric oxide; NOX2, NADPH oxidase type 2; nNOS, neuronal nitric oxide synthase; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PLB, phospholamban; ROS, reactive oxygen species; RyR, ryanodine receptor; SERCA, SR Ca²⁺-ATPase; SR, sarcoplasmic reticulum.