Neonatal -adrenoceptors (-ARs) are resistant to agonist-induced desensitization. We examined the functioning of G_i and G_s after repeated administration of -AR agonists to newborn rats. Isoproterenol (₁/₂ agonist) obtunded G_i function in the heart but not the liver; in contrast, terbutaline, a ₂-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 (S) 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 -AR cell signaling in the face of excessive or prolonged stimulation; these mechanisms also contribute to tissue selectivity of the effects of -agonists with divergent potencies toward different -AR subtypes.