Figure 11. The effects of β₁-adrenoceptor stimulation on ryanodine receptors.

Panel A: Markov model of ryanodine receptors. State diagram consists of two similar sub-diagrams for non-phosphorylated (upper sub-diagram) and phosphorylated states (lower sub-diagram). C₁ and C₂ are closed states; O₁ and O₂ are open states; C_1p and C_2p are closed phosphorylated states; O_1p and O_2p are open phosphorylated states. The rate constants from C₁ to O₁, from O₁ to O₂, from C_1p to O_1p, and from O_1p to O_2p are Ca²⁺-dependent; and k_phos and k_deph are the phosphorylation and dephosphorylation rates, respectively (see Appendix S1). Panel B: Time course of the relative phosphorylation level of RyRs upon activation of the β₁-adrenergic signaling system. Experimental data of Xiao et al. [94] (filled circles) are obtained upon stimulation of rat ventricular myocytes with 1 µM isoproterenol; experimental data of Takasago et al. [95] (filled squares) are obtained from canine ventricular myocytes with endogenous PKA by application of [γ-³²P]ATP. Modeling data are obtained by application of 1 µM isoproterenol. Increase in phosphorylation level is determined as a fractional increase related to the maximum increase in phosphorylation of RyRs after activation of the β₁-adrenergic signaling system. Panel C: Relative phosphorylation level of RyRs at different concentrations of isoproterenol. Experimental data of Xiao et al. [94] (filled circles) obtained upon stimulation of rat ventricular myocytes for 15 minutes. Simulation data are obtained after 10-minute exposure to different concentrations of isoproterenol. Panel D: Effects of PKA on opening probability of RyRs as function of cytosolic Ca²⁺ concentration. Experimental data of Xiao et al. [93] are obtained for cardiac RyRs upon application of active (filled circles) and boiled (unfilled circles) PKA at relatively small luminal Ca²⁺ of 45 nM; experimental data of Xiao et al. [96] (filled squares) for RyRs are obtained from mouse ventricular myocytes. Simulation data for mouse ventricular myocytes in the absence and presence of PKA are obtained at intracellular [Ca²⁺]_i concentration ranged from 0.01 to 10 µM and are shown by dashed and solid lines. Experimental data obtained at small luminal Ca²⁺ concentration shows larger sensitivity of RyRs to cytosolic Ca²⁺.