Figure 6.

Numerical modeling of GPCR modulation of AP firing rate in rabbit SANC. A: The coupled-clock ML model prediction for the mechanisms of spontaneous Ca²⁺ release in rabbit SANC and their modulation by β-AR (ISO) or ChR (ACh) stimulation. Panels show model simulations of simultaneous changes in membrane potentials (V_m), submembrane [Ca²⁺] (Ca_sub), [Ca²⁺] in junctional (i.e. Ca²⁺ releasing) SR (Ca_jSR), and Ca²⁺ release flux (j_SRCarel). The Ca²⁺ release becomes more synchronized and occurs earlier in case of ISO, but less synchronized and occurs later in case of ACh, as reflected by times to half maximum of the diastolic release (in j_SRCarel panel). Modified from (43). B: Only the ML model predicts the full scale of β-AR stimulation effect reported within the range of 25–30% increase in AP firing rate in rabbit SANC. SANC models, lacking diastolic Ca²⁺ release, substantially underestimate the effect of β-AR stimulation. Models are labeled as follows: “Dokos” (79), “Zhang” (80), “Kurata”(66). Respective bars show the model predictions for the effects of experimentally reported changes of M-clock parameters, doubling the capability of SR Ca²⁺ pumping, P_up, or both changes combined. Spontaneous rate change was negligible (within 0.1%) in Zhang et al. model (Note this model has no Ca²⁺ dynamics, i.e. [Ca²⁺]=const). Absolute AP firing rates predicted by the models are shown by labels at the respective bars. Modified from (43).