Overexpression of β2-adrenergic receptors cAMP-dependent protein kinase phosphorylates and modulates slow delayed rectifier potassium channels expressed in murine heart -: Evidence for receptor/channel co-localization

The cardiac slow delayed rectifier potassium channel (I-Ks), comprised of alpha (KCNQ1) and beta (KCNE1) subunits, is regulated by sympathetic nervous stimulation, with activation of beta-adrenergic receptors PKA phosphorylating IKs channels. We examined the effects of beta(2)-adrenergic receptors (beta(2)-AR) on I-Ks in cardiac ventricular myocytes from transgenic mice expressing fusion proteins of I-Ks subunits and hbeta(2)-ARs. KCNQ1 and beta(2)-ARs were localized to the same subcellular regions, sharing intimate localization within nanometers of each other. In I-Ks/B-2-AR myocytes, I-Ks density was increased, and activation shifted in the hyperpolarizing direction; I-Ks was not further modulated by exposure to isoproterenol, and KCNQ1 was found to be PKA-phosphorylated. Conversely, beta(2)-AR overexpression did not affect L-type calcium channel current (I-CaL) under basal conditions with ICaL remaining responsive to cAMP. These data indicate intimate association of KCNQ1 and beta(2)-ARs and that beta(2)-AR signaling can modulate the function of I-Ks channels under conditions of increased beta(2)-AR expression, even in the absence of exogenous beta(2)-AR agonist.