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

In a previous paper published by Wang and Lipsius in 1995, it was discovered that exposing atrial myocytes to isoproterenol (ISO), which stimulates beta-adrenergic receptors and results in the accumulation of Ca²⁺, enhanced subsequent muscarinic receptor stimulation by acetylcholine (ACh) and therefore increased K⁺ conductance. In this study, Wang et al. have deduced the mechanisms underlying this phenomenon.

There are two types of beta-adrenergic receptors, beta₁-AR and beta₂-AR, and ISO is a non-selective agonist which will bind to and stimulate both types of receptor. Both beta-ARs are present in atrial myocytes, and each type triggers a different signal transduction pathway. Beta₁-AR is exclusively coupled to a G_s-protein which activates adenylate cyclase (AC). Active AC catalyses the conversion of ATP to cAMP, which then activates protein kinase A (PKA). In turn this enzyme phosphorylates the L-type Ca²⁺ channels and I_Ca is enhanced. By contrast, beta₂-AR signalling appears to be more diverse. Beta₂-ARs are coupled to both G_i- and G_s-proteins. Activation of the G_s-protein triggers the same signal transduction pathway as described above, while activation of the G_i-protein stimulates a different pathway (see the figure below). In this pathway, stimulation of phosphatidylinositol 3'-kinase (PI-3K), activates Akt mediated phosphorylation of constitutive nitric oxide synthase (eNOS), resulting in the production of nitric oxide (NO). NO stimulates guanylate cyclase (GC) to elicit cGMP-induced inhibition of phosphodiesterase (PDE) type III activity, which in turn enhances cAMP-dependent stimulation of I_Ca,L .

Both beta₁-ARs and beta₂-ARs stimulate cAMP and enhance I_Ca,L via the G_s-protein-AC-cAMP-PKA pathway. However, this cAMP has no effect on the ACh-induced activation ofI_KATP. Only the cAMP produced by the beta₂-ARs, acting via the G_i-protein and NO signalling mediate ACh-induced activation of I_K,ATP . This suggests that compartmentalised pools of cAMP generated via the different signalling pathways target different ion channels.

The description of this signal transduction pathway was based on a paper by Wang et al. (2002), which investigates the role of ISO in ACh-induced activation of ATP-sensitive K⁺ current (I_KATP). 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, Elena N. Dedkova, Susan F. Steinberg, Lothar A. Blatter, and Stephen L. Lipsius, 2002, The Journal of General Physiology , 119, 69-82. (Full text and PDF versions of the article are available to subscribers on The Journal of General Physiology website.)

Signal Transduction Pathway Diagram

Schematic diagram of the ISO signalling cascade that enhances ACh-induced IKATP.

• wang_2002_version01.cellml