Neonatal ß-adrenoceptors (ß-ARs) are resistant to agonist-induced desensitization. We examined the functioning of G_i and G_s after repeated administration of ß-AR agonists to newborn rats. Isoproterenol (ß₁/ß₂-agonist), obtunded G_i function in the heart but not the liver; in contrast, terbutaline, a ß₂-selective agonist, enhanced G_i function. Isoproterenol, but not terbutaline, increased membrane-associated G_s, which would enhance receptor function. In addition, isoproterenol increased, and terbutaline maintained, the proportion of the short splice-variant of G_s in the membrane fraction; G_sS is functionally more active than the long splice-variant. Either isoproterenol or terbutaline treatment increased G_s in the cytosolic fraction, a characteristic usually associated with desensitization in the adult. Decreased G_i activity, coupled with increased membrane-associated G_s concentrations and maintenance or increases in membrane G_sS, provide strong evidence that unique effects on G-protein function underlie the ability of the immature organism to sustain ß-AR cell signaling in the face of excessive or prolonged stimulation; these mechanisms also contribute to tissue-selectivity of the effects of ß-agonists with divergent potencies toward different ß-AR subtypes.