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The cardiac slow delayed rectifier potassium channel (IKs), comprised of α (KCNQ1) and β (KCNE1) subunits, is regulated by sympathetic nervous stimulation, with activation of β-adrenergic receptors PKA phosphorylating IKs channels. We examined the effects of β2-adrenergic receptors (β2-AR) on IKs in cardiac ventricular myocytes from transgenic mice expressing fusion proteins of IKs subunits and hβ2-ARs. KCNQ1 and β2-ARs were localized to the same subcellular regions, sharing intimate localization within nanometers of each other. In IKs/B2-AR myocytes, IKs density was increased, and activation shifted in the hyperpolarizing direction; IKs was not further modulated by exposure to isoproterenol, and KCNQ1 was found to be PKA-phosphorylated. Conversely, β2-AR overexpression did not affect L-type calcium channel current (ICaL) under basal conditions with ICaL remaining responsive to cAMP. These data indicate intimate association of KCNQ1 and β2-ARs and that β2-AR signaling can modulate the function of IKs channels under conditions of increased β2-AR expression, even in the absence of exogenous β-AR agonist. [ABSTRACT FROM AUTHOR]