Model Status

This CellML model still contains the reaction element. We have been unable to recode this model to remove the reaction element because the published paper does not contain a quantitative model. Therefore this CellML model is a purely qualitative model it and contains no mathematical description of the pathways defined. All the rates and concentrations have been set to 1.0.

Signal Transduction Pathway

Acetylcholine (ACh) affects cardiac function through several signal transduction pathways. It binds to muscarinic receptors (M1 and M2) coupled to Gi-proteins to directly activate K+ channel currents (IK,ACh), and also ATP-sensitive K+ currents (IK,ATP). The mechanisms underlying the activation of IK,ACh are believed to be relatively simple. The binding of ACh1 to the cell surface receptor M2 activates the coupled Gi-protein, which then in turn directly activates the ACh-sensitive K+ channel and enhances K+ conductance and IK,ACh.

The mechanisms underlying IK,ACh stimulation are thought to be more complex. ACh2 binds to the cell surface receptor M1 and acts via a Gi-protein to trigger a signal transduction cascade which results in the activation of IK,ATP. It also appears that previous exposure to isoproterenol (ISO), which stimulates beta-adrenergic receptors and results in the accumulation of Ca2+, can enhance ACh activation of IK,ATP.

Activation of phospholipase C (PLC) results in the hydrolysis of phosphatidylinositol (PIP2) to produce inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 activates Ca2+ channels in the endoplasmic reticulum (ER) triggering the release of Ca2+ from intracellular stores. This Ca2+ and DAG then activate protein kinase C (PKC), which in turn phosphorylates K+ channels, and increases IK,ATP (see Figure 1 below).

The mechanisms underlying the ISO enhancement of ACh-induced IK,ATP activation were not fully deduced by the experiments carried out in this study. For the full explanation of the mechanisms please refer to model by Wang et al. published in 2002. The description of this signal transduction pathway in the current CellML model was based on a paper by Wang and Lipsius (1995), which investigates the influence of beta-adrenergic stimulation on IK,ATP in atrial myocytes. The complete original paper reference is cited below:

Beta₂-Adrenergic Receptor Signaling Acts via NO Release to Mediate ACh-induced Activation of ATP-sensitive K⁺ Current in Cat Atrial Myocytes, Yong G. Wang and Stephen L. Lipsius, 1995, Circulation Research , 77, 565-574. (A Full text version of the article is available to subscribers on Circulation Research website.) PubMed ID: 7641326

Signal Transduction Pathway Diagram

Schematic diagram of the ACh signalling cascades that stimulate IK,ACh and IK,ATP.

• wang_lipsius_1995_version01.cellml