Figure 2
cAMP and cGMP pathways. Reaction pathways triggered by sympathetic and parasympathetic neural stimuli invoking cAMP [25] and cGMP-mediated [26] modulation of various sub-cellular targets respectively. ACh-mediated effects of junctional receptor on N a+ current and background N a+ current and extrajunctional muscarinic M 2/K ACh receptor on I K,A C h (direct muscarinic pathway) and cAMP-mediated effects of β-adrenoreceptor (adrenergic pathway) and cholinergic M 2/ADC receptor (indirect muscarinic pathway) on L-type C a2+ (I C a,L), K+ (I K ), hyperpolarization-activated (I f ), and N a+/ K+ (I NaK )currents are shown ‡. Although cAMP-dependent modulation of I C a,L and I up are known to be PKA-mediated, we make use of a lumped cAMP term to model this influence. A similar lumped cAMP term is employed to modulate phosphorylation of PLB which in turn affects the SERCA pump. ACh triggered NO-mediated synthesis of cGMP by sGC is modeled employing a 3-state model for sGC transition based on Yang et al. [26]. cGMP is involved in suppressing cAMP activity via PDE. cGMP also enhances I PMCA , C a2+ activated K+ channel (I KCa ) and suppresses IC a,L, Ic y t,s e r c a via PKG (not explicitly modeled, but lumped into a cGMP term). ‡ The rat ventricular cell model used in this study is however limited to C a2+ related channel, exchanger and pumps (IC a,L, I NaCa , I PMCA and Ic y t,s e r c a), while lacking exclusive N a+ or K+ related channels and transporters (as shown in Figure 2, Krishna et al. [15]). The part of the model describing cAMP-mediated pathway used in our study is highlighted (blue).