The Mechanisms Underlying Beta-Adrenergic Enhancement of Acetylcholine-Induced ATP-Sensitive K+ Current in Atrial Myocytes

In a previous paper published by Wang and Lipsius in 1995 (see The ACh Cascade Description ), 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 Figure 1 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.)