Isoprenaline can activate the acetylcholine-induced K+ current in canine atrial myocytes via Gs-derived βγ subunits

G protein βγ subunits activate the acetylcholine-induced potassium current Ik,ach. There is no evidence of specificity at the level of the βγ subunits. Therefore all G protein-coupled receptors in atrial myocytes should be able to activate Ik,ach. Paradoxically, it is often stated that isoprenaline does not activate Ik,ach. Rationales to explain this negative result include insufficient concentrations of Gs in the atrium or restricted access of Gs-derived βγ subunits to the Ik,ach channel. We took advantage of a non-specific increase in Gs that results after infection with adenovirus.Adenoviral infection unmasked a 1 μm isoprenaline-induced Ik,ach which was prevented by propranolol. Isoprenaline occasionally activated Ik,ach in uninfected and freshly dissociated atrial myocytes but the effect was larger and more consistent in infected myocytes.Pertussis toxin pretreatment (100 ng ml−1 overnight) did not block the effect of isoprenaline. The effect of isoprenaline became persistent if cells were pretreated with cholera toxin (200 ng nl−1).Signal transduction events distal to adenylyl cyclase were not involved in isoprenaline-induced Ik,ach. Forskolin (10 μm) did not activate Ik,ach. Inhibition of adenylyl cyclase with cytoplasmic application of 300 μm 2′-deoxyadenosine 3′-monophosphate did not prevent the activation of Ik,ach by isoprenaline.Cytoplasmic application of a βγ binding peptide derived from the C terminus of β-adrenergic receptor kinase 1 (50 μm) prevented the effect of isoprenaline on Ik,ach. The peptide did not prevent the stimulation of the L-type calcium current by isoprenaline.The results indicate that β-adrenoceptors can activate Ik,ach in atrial myocytes through the release of βγ subunits from Gs